RESUMO
Telmisartan, a selective inhibitor of angiotensin II receptor type 1 (AT1), demonstrates nonlinear pharmacokinetics (PK) when orally administered in ascending doses to healthy volunteers, but the underlying mechanisms remain unclear. This study presents a physiologically based pharmacokinetic model integrated with target-mediated drug disposition (TMDD-PBPK model) to explore the mechanism of its nonlinear PK. We employed the Cluster-Gauss Newton method for top-down analysis, estimating the in vivo Km,OATP1B3 (Michaelis-Menten constant for telmisartan hepatic uptake via Organic Anion Transporting Polypeptide 1B3) to be 2.0-5.7 nM. This range is significantly lower than the reported in vitro value of 810 nM, obtained in 0.3% human serum albumin (HSA) conditions. Further validation was achieved through in vitro assessment in plated human hepatocytes with 4.5% HSA, showing a Km of 4.5 nM. These results underscore the importance of albumin-mediated uptake effect for the hepatic uptake of telmisartan. Our TMDD-PBPK model, developed through a "middle-out" approach, underwent sensitivity analysis to identify key factors in the nonlinear PK of telmisartan. We found that the nonlinearity in the area under the concentration-time curve (AUC) and/or maximum concentration (Cmax) of telmisartan is sensitive to Km,OATP1B3 across all dosages. Additionally, the dissociation constant (Kd) for telmisartan binding to the AT1 receptor, along with its receptor abundance, notably influences PK at lower doses (below 20 mg). In conclusion, the nonlinear PK of telmisartan appears primarily driven by hepatic uptake saturation across all dose ranges and by AT1-receptor binding saturation, notably at lower doses.
Assuntos
Hepatócitos , Modelos Biológicos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Telmisartan , Telmisartan/farmacocinética , Telmisartan/administração & dosagem , Humanos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Hepatócitos/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Fígado/metabolismo , Dinâmica não Linear , Benzimidazóis/farmacocinética , Benzimidazóis/administração & dosagem , Benzoatos/farmacocinética , Benzoatos/administração & dosagem , Voluntários Saudáveis , Administração OralRESUMO
Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib Cmax but did lead to a 26% increase in sotorasib AUCinf. CYP3A4 induction decreased sotorasib Cmax by 35% and AUCinf by 51%. OATP1B1/3 inhibition decreased sotorasib Cmax and AUCinf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.
Assuntos
Indutores do Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interações Medicamentosas , Transportador 1 de Ânion Orgânico Específico do Fígado , Rifampina , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Adulto , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Rifampina/farmacologia , Rifampina/administração & dosagem , Indutores do Citocromo P-450 CYP3A/farmacologia , Feminino , Adulto Jovem , Administração Oral , Pessoa de Meia-Idade , Voluntários Saudáveis , Área Sob a Curva , Itraconazol/farmacologia , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Compostos de Espiro/farmacocinética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacologiaRESUMO
Daprodustat is the first oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B-mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically-based PK (PBPK) modeling of its drug-drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by OATP1B1/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single-dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable 9.9 ± 1.2-fold (P < 0.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady-state was also reduced by 5.0 ± 1.1-fold, whereas the half-life change was minimal (1.5-fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B-CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18-fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well-captured by the model. CYP2C8 and/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate-to-strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation.
Assuntos
Citocromo P-450 CYP2C8 , Interações Medicamentosas , Hepatócitos , Transportador 1 de Ânion Orgânico Específico do Fígado , Insuficiência Renal Crônica , Rifampina , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Adulto , Animais , Feminino , Humanos , Masculino , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2C8/farmacocinética , Glicina/análogos & derivados , Glicina/farmacocinética , Células HEK293 , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatopatias/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Macaca fascicularis , Insuficiência Renal Crônica/metabolismo , Rifampina/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidoresRESUMO
Elagolix is an oral gonadotropin-releasing hormone receptor antagonist indicated for the management of endometriosis-associated pain and in combination with estradiol/norethindrone acetate indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Elagolix coadministered with estradiol/norethindrone acetate is in late-stage development for the management of heavy menstrual bleeding associated with uterine fibroids. Based on the in vitro profile of elagolix metabolism and disposition, 9 drug-drug interaction (DDI) studies evaluating the victim and perpetrator characteristics of elagolix were conducted in 144 healthy volunteers. As a victim of cytochrome P450 (CYPs) and transporter-mediated DDIs, elagolix area under the curve (AUC) increased by â¼2-fold following coadministration with ketoconazole and by â¼5- and â¼2-fold with single and multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased midazolam AUC (90% confidence interval) by 54% (50%-59%) and increased digoxin AUC by 32% (23%-41%). Elagolix decreased rosuvastatin AUC by 40% (29%-50%). No clinically significant changes in exposure on coadministration with sertraline or fluconazole occurred. A elagolix 150-mg once-daily regimen should be limited to 6 months with strong CYP3A inhibitors and rifampin because of the potential increase in bone mineral density loss, as described in the drug label. A 200-mg twice-daily regimen is recommended for no more than 1 month with strong CYP3A inhibitors and not recommended with rifampin. Elagolix is contraindicated with strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when coadministered with elagolix, and individualize therapy based on patient response. Clinical monitoring is recommended for P-glycoprotein substrates with a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when coadministered.
Assuntos
Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Receptores LHRH/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/agonistas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Citocromo P-450 CYP2B6/metabolismo , Indutores do Citocromo P-450 CYP2B6/administração & dosagem , Indutores do Citocromo P-450 CYP2B6/farmacocinética , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Inibidores do Citocromo P-450 CYP2C9/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Hidrocarbonetos Fluorados/sangue , Hidrocarbonetos Fluorados/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Pré-Menopausa , Pirimidinas/sangue , Pirimidinas/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Adulto JovemRESUMO
PURPOSE: Scutellarin, a flavonoid derived from the plant Erigeron breviscapus, is currently widely used to treat cerebrovascular diseases, liver-related diseases, and hyperlipidemia in china and other East Asian countries. This study was to investigate the effect of scutellarin on the uptake of rosuvastatin in HEK293T cells expressing human organic anion transporting polypeptide 1B3 (hOATP1B3) and rat OATP1B2 (rOATP1B2), respectively, and the effect of scutellarin on the pharmacokinetics of rosuvastatin in rats. METHODS: The newly established HEK293T cells expressing hOATP1B3 and rOATP1B2 were used to examine the effects of scutellarin and positive controls on in vitro rosuvastatin transport. After co-feeding with scutellarin, the rosuvastatin area under the plasma concentration-time curve (AUC0-24h), the peak plasma drug concentration (Cmax), elimination half-life (t1/2), time to reach Cmax (tmax), clearance (CL) and apparent clearance (CL/F) of rosuvastatin were determined in rats. RESULTS: Scutellarin inhibited hOATP1B3- and rOATP1B2-mediated rosuvastatin uptake (IC50: 45.54 ± 6.67 µM and 27.58 ± 3.97 µM) in vitro in a concentration-dependent manner. After co-feeding with scutellarin, the AUC0-24h and Cmax of rosuvastatin in rats increased to 27.4% and 37.7%, respectively. The t1/2 and tmax of rosuvastatin showed no significant change. Moreover, scutellarin caused 29.2% and 28.1% decrease in the CL and CL/F of rosuvastatin. CONCLUSION: Scutellarin may inhibit the hOATP1B3- and rOATP1B2-mediated transport of rosuvastatin in vitro, and exerts a moderate inhibitory effect on the pharmacokinetics of rosuvastatin in rats. Scutellarin is highly likely to participate in drug-drug interactions, as mediated by OATP1B3 in humans.
Assuntos
Apigenina/farmacologia , Glucuronatos/farmacologia , Rosuvastatina Cálcica/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Animais , Área Sob a Curva , Interações Medicamentosas , Células HEK293 , Meia-Vida , Humanos , Masculino , Ratos , Proteínas Recombinantes/metabolismo , Rosuvastatina Cálcica/administração & dosagem , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismoRESUMO
Organic anion-transporting polypeptide (OATP) 1B1/3-mediated drug-drug interaction (DDI) potential is evaluated in vivo with rosuvastatin (RST) as a probe substrate in clinical studies. We calibrated our assay with RST and estradiol 17-ß-D-glucuronide (E217ßG)/cholecystokinin-8 (CCK8) as in vitro probes for qualitative and quantitative prediction of OATP1B-mediated DDI potential for RST. In vitro OATP1B1/1B3 inhibition using E217ßG and CCK8 yielded higher area under the curve (AUC) ratio (AUCR) values numerically with the static model, but all probes performed similarly from a qualitative cutoff-based prediction, as described in regulatory guidances. However, the magnitudes of DDI were not captured satisfactorily. Considering that clearance of RST is also mediated by gut breast cancer resistance protein (BCRP), inhibition of BCRP was also incorporated in the DDI prediction if the gut inhibitor concentrations were 10 × IC50 for BCRP inhibition. This combined static model closely predicted the magnitude of RST DDI with root-mean-square error values of 0.767-0.812 and 1.24-1.31 with and without BCRP inhibition, respectively, for in vitro-in vivo correlation of DDI. Physiologically based pharmacokinetic (PBPK) modeling was also used to simulate DDI between RST and rifampicin, asunaprevir, and velpatasvir. Predicted AUCR for rifampicin and asunaprevir was within 1.5-fold of that observed, whereas that for velpatasvir showed a 2-fold underprediction. Overall, the combined static model incorporating both OATP1B and BCRP inhibition provides a quick and simple mathematical approach to quantitatively predict the magnitude of transporter-mediated DDI for RST for routine application. PBPK complements the static model and provides a framework for studying molecules when a dynamic model is needed. SIGNIFICANCE STATEMENT: Using 22 drugs, we show that a static model for organic anion-transporting polypeptide (OATP) 1B1/1B3 inhibition can qualitatively predict potential for drug-drug interaction (DDI) using a cutoff-based approach, as in regulatory guidances. However, consideration of both OATP1B1/3 and gut breast cancer resistance protein inhibition provided a better prediction of the magnitude of the transporter-mediated DDI of these inhibitors with rosuvastatin. Based on these results, we have proposed an empirical mechanistic-static approach for a more reliable prediction of transporter-mediated DDI liability with rosuvastatin that drug development teams can leverage.
Assuntos
Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Modelos Biológicos , Rosuvastatina Cálcica/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Área Sob a Curva , Colecistocinina/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Estradiol/análogos & derivados , Estradiol/farmacocinética , Células HEK293 , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Fragmentos de Peptídeos/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidoresRESUMO
Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux.
Assuntos
Fármacos Anti-HIV/metabolismo , Maraviroc/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Placenta/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacologia , Animais , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacologia , Linhagem Celular Tumoral , Cães , Interações Medicamentosas , Feminino , Regulação da Expressão Gênica , Humanos , Células Madin Darby de Rim Canino , Maraviroc/sangue , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/genética , Perfusão , Placenta/efeitos dos fármacos , Circulação Placentária , Gravidez , Ritonavir/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
Probenecid (PROB) is a clinical probe inhibitor of renal organic anion transporter (OAT) 1 and OAT3 that inhibits in vitro activity of hepatic drug transporters OATP1B1 and OATP1B3. It was hypothesized that PROB could potentially affect the disposition of OATP1B drug substrates. The plasma levels of the OATP1B endogenous biomarker candidates, including coproporphyrin I (CPI), CPIII, hexadecanedioate (HDA), and tetradecanedioate (TDA), were examined in 14 healthy subjects treated with PROB. After oral administration with 1000 mg PROB alone and in combination with furosemide (FSM), AUC (0-24 h) values were 1.39 ± 0.21-fold and 1.57 ± 0.41-fold higher than predose levels for CPI and 1.34 ± 0.16-fold and 1.45 ± 0.57-fold higher for CPIII. Despite increased systemic exposures, no decreases in CPI and CPIII renal clearance were observed (0.97 ± 0.38-fold and 1.16 ± 0.51-fold for CPI, and 1.34 ± 0.53-fold and 1.50 ± 0.69-fold for CPIII, respectively). These results suggest that the increase of CP systemic exposure is caused by OATP1B inhibition. Consistent with this hypothesis, PROB inhibited OATP1B1- and OATP1B3-mediated transport of CPI in a concentration-dependent manner, with IC50 values of 167 ± 42.0 and 76.0 ± 17.2 µM, respectively, in transporter-overexpressing human embryonic kidney cell assay. The inhibition potential was further confirmed by CPI and CPIII hepatocyte uptake experiments. In contrast, administration of PROB alone did not change AUC (0-24 h) of HDA and TDA relative to prestudy levels, although the administration of PROB in combination with FSM increased HDA and TDA levels compared with FSM alone (1.02 ± 0.18-fold and 0.90 ± 0.20-fold vs. 1.71 ± 0.43-fold and 1.62 ± 0.40-fold). Taken together, these findings indicate that PROB displays weak OATP1B inhibitory effects in vivo and that coproporphyrin is a sensitive endogenous probe of OATP1B inhibition. This study provides an explanation for the heretofore unknown mechanism responsible for PROB's interaction with other xenobiotics. SIGNIFICANCE STATEMENT: This study suggested that PROB is a weak clinical inhibitor of OATP1B based on the totality of evidence from the clinical interaction between PROB and CP and the in vitro inhibitory effect of PROB on OATP1B-mediated CP uptake. It demonstrates a new methodology of utilizing endogenous biomarkers to evaluate complex drug-drug interaction, providing explanation for the heretofore unknown mechanism responsible for PROB's inhibition. It provides evidence to strengthen the claim that CP is a sensitive circulating endogenous biomarker of OATP1B inhibition.
Assuntos
Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Probenecid/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Administração Oral , Área Sob a Curva , Coproporfirinas/sangue , Coproporfirinas/metabolismo , Coproporfirinas/urina , Interações Medicamentosas , Feminino , Furosemida/farmacologia , Células HEK293 , Voluntários Saudáveis , Hepatócitos , Humanos , Concentração Inibidora 50 , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismoRESUMO
Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are the primary hepatic transporters responsible for uptake of drugs into the liver and, as such, an area of growing research focus. Currently, evaluation of these transporters as potential mediators of drug-drug interactions (DDIs) is recommended by regulatory agencies worldwide during the drug development process. Despite the growing focus on OATP1B1/1B3 as mediators of DDIs, only 2 drugs are recommended as index inhibitors for use in clinical studies, single-dose rifampin and cyclosporine, each with limitations for the utility of the resulting data. In this study a thorough analysis of the available in vitro and clinical data was conducted to identify drugs that are clinically relevant inhibitors of OATP1B1/1B3 and, from those, to select any novel index inhibitors. A total of 13 drugs and 16 combination products were identified as clinical inhibitors of OATP1B1/1B3, showing significant changes in exposure for sensitive substrates of the transporters, with strong supporting in vitro evidence. Although none of the identified inhibitors qualified as index inhibitors, this study confirmed the utility of cyclosporine and single-dose rifampin as index inhibitors to evaluate the effect of broad, multiple-pathway inhibition and more selective OATP1B1/1B3 inhibition, respectively.
Assuntos
Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Animais , Transporte Biológico , Ciclosporina/farmacologia , Bases de Dados de Produtos Farmacêuticos , Interações Medicamentosas , Rotulagem de Medicamentos , Humanos , Oócitos/efeitos dos fármacos , Rifampina/farmacologia , Estados Unidos , United States Food and Drug Administration , Xenopus laevisRESUMO
Paclitaxel has been considered to cause OATP1B-mediated drug-drug interactions at therapeutic doses; however, its clinical relevance has not been demonstrated. This study aimed to elucidate in vivo inhibition potency of paclitaxel against OATP1B1 and OATP1B3 using endogenous OATP1B biomarkers. Paclitaxel is an inhibitor of OATP1B1 and OATP1B3, with Ki of 0.579 ± 0.107 and 5.29 ± 3.87 µM, respectively. Preincubation potentiated its inhibitory effect on both OATP1B1 and OATP1B3, with Ki of 0.154 ± 0.031 and 0.624 ± 0.183 µM, respectively. Ten patients with non-small cell lung cancer who received 200 mg/m2 of paclitaxel by a 3-hour infusion were recruited. Plasma concentrations of 10 endogenous OATP1B biomarkers-namely, coproporphyrin I, coproporphyrin III, glycochenodeoxycholate-3-sulfate, glycochenodeoxycholate-3-glucuronide, glycodeoxycholate-3-sulfate, glycodeoxycholate-3-glucuronide, lithocholate-3-sulfate, glycolithocholate-3-sulfate, taurolithocholate-3-sulfate, and chenodeoxycholate-24-glucuronide-were determined in the patients with non-small cell lung cancer on the day before paclitaxel administration and after the end of paclitaxel infusion for 7 hours. Paclitaxel increased the area under the plasma concentration-time curve (AUC) of the endogenous biomarkers 2- to 4-fold, although a few patients did not show any increment in the AUC ratios of lithocholate-3-sulfate, glycolithocholate-3-sulfate, and taurolithocholate-3-sulfate. Therapeutic doses of paclitaxel for the treatment of non-small cell lung cancer (200 mg/m2) will cause significant OATP1B1 inhibition during and at the end of the infusion. This is the first demonstration that endogenous OATP1B biomarkers could serve as surrogate biomarkers in patients. SIGNIFICANCE STATEMENT: Endogenous biomarkers can address practical and ethical issues in elucidating transporter-mediated drug-drug interaction (DDI) risks of anticancer drugs clinically. We could elucidate a significant increment of the plasma concentrations of endogenous OATP1B biomarkers after a 3-hour infusion (200 mg/m2) of paclitaxel, a time-dependent inhibitor of OATP1B, in patients with non-small cell lung cancer. The endogenous OATP1B biomarkers are useful to assess the possibility of OATP1B-mediated DDIs in patients and help in appropriately designing a dosing schedule to avoid the DDIs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Idoso , Área Sob a Curva , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Interações Medicamentosas , Feminino , Células HEK293 , Humanos , Infusões Intravenosas , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/uso terapêutico , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Proteínas Recombinantes/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Resultado do TratamentoRESUMO
In vitro studies have indicated that the P2Y12 receptor antagonist selatogrel is a substrate of organic anion-transporting-polypeptide (OATP)1B1 and OATP1B3 that are known to mediate hepatic uptake. Selatogrel is primarily eliminated via the biliary route. Therefore, the study aim was to investigate the effect of rifampin-mediated OATP1B1 and OATP1B3 inhibition on the pharmacokinetics (PK) of selatogrel. This was a randomized, double-blind, placebo-controlled, two-period, crossover study in 14 healthy subjects. In each period, a single subcutaneous dose of 4 mg selatogrel was administered, either immediately after a single intravenous 30 minutes infusion of 600 mg rifampin or after placebo. Plasma samples were collected for 36 hours and analyzed using a validated liquid chromatography-tandem mass spectrometry method. PK parameters of selatogrel were calculated using noncompartmental analysis. The effect of rifampin was explored based on geometric mean peak plasma concentration (Cmax ) and area under the concentration curve from zero to infinity (AUC0-∞ ) ratios and for time of maximum plasma concentration (Tmax ) by Wilcoxon signed rank test. In addition, the safety and tolerability of the study treatments were evaluated. The geometric mean ratios of Cmax and AUC0-∞ were 1.19 (90% confidence interval (CI) 1.11-1.28) and 1.43 (90% CI 1.36-1.51), respectively, indicating a minor selatogrel exposure increase when administered after an infusion of rifampin compared with placebo. Rifampin administration did not affect terminal half-life (t½ ) or Tmax of selatogrel. All study treatments were safe and well-tolerated. A single dose of 600 mg rifampin, a potent OATP1B1/1B3 inhibitor, did not impact the PK of selatogrel to a clinically relevant extent suggesting that OATP1B1 and OATP1B3 transporters do not play a major role in the elimination of selatogrel.
Assuntos
Organofosfonatos/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Pirimidinas/farmacocinética , Rifampina/farmacocinética , Adolescente , Adulto , Idoso , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Interações Medicamentosas , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Organofosfonatos/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Pirimidinas/administração & dosagem , Receptores Purinérgicos P2Y12/metabolismo , Rifampina/administração & dosagem , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Adulto JovemRESUMO
As the research into the organic anion transporting polypeptides (OATPs) continues to grow, it is important to ensure that the data generated are accurate and reproducible. In the in vitro evaluation of OATP1B1/1B3 inhibition, there are many variables that can contribute to variability in the resulting inhibition constants, which can then, in turn, contribute to variable results when clinical predictions (R-values) are performed. Currently, the only experimental condition recommended by the US Food and Drug Administration (FDA) is the inclusion of a pre-incubation period.1 To identify other potential sources of variability, a descriptive analysis of available in vitro inhibition data was completed. For each of the 21 substrate/inhibitor pairs evaluated, cell type and pre-incubation were found to have the greatest effect on half-maximal inhibitory concentration (IC50 ) variability. Indeed, when only HEK293 cells and co-incubation conditions were included, the observed variability for the entire data set (highest IC50 /lowest) was reduced from 12.4 to 5.2. The choice of probe substrate used in the study also had a significant effect on inhibitor constant variability. Interestingly, despite the broad range of inhibitory constants identified, these two factors showed little effect on the calculated R-values relative to the FDA evaluation cutoff of 1.1 triggering a clinical evaluation for the inhibitors evaluated. However, because of the small data set available, further research is needed to confirm these preliminary results and define best practice for the study of OATPs.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Técnicas de Cultura de Células/métodos , Técnicas de Cultura de Células/normas , Ciclosporina/farmacologia , Conjuntos de Dados como Assunto , Avaliação Pré-Clínica de Medicamentos/normas , Interações Medicamentosas , Genfibrozila/farmacologia , Guias como Assunto , Células HEK293 , Humanos , Concentração Inibidora 50 , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Reprodutibilidade dos Testes , Rifampina/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Estados Unidos , United States Food and Drug Administration/normasRESUMO
Rhinacanthin-C is a major active constituent in Rhinacanthus nasutus (L.) Kurz, a plant widely used in herbal remedies. Its potential for pharmacokinetic herb-drug interaction may exist with drug transporters and drug metabolizing enzymes. This study assessed the possibility for rhinacanthin-C-mediated drug interaction by determining its inhibitory effects against major human efflux and influx drug transporters as well as various human cytochrome P450(CYP) isoforms. Rhinacanthin-C demonstrated a moderate permeability through the Caco-2 monolayers [Papp (AP-to-BL) = 1.26 × 10-6 cm/s]. It significantly inhibited transport mediated by both P-glycoprotein (P-gp) (IC50 = 5.20 µM) and breast cancer resistance protein (BCRP) (IC50 = 0.83 µM) across Caco-2 and BCRP-overexpressing Madin-Darby canine kidney II cells (MDCKII) cells. This compound also strongly inhibited uptake mediated by organic anion-transporting polypeptide 1B1 (OATP1B1) (IC50 = 0.70 µM) and OATP1B3 (IC50 = 3.95 µM) in OATP1B-overexpressing HEK cells. In addition to its inhibitory effect on these drug transporters, rhinacanthin-C significantly inhibited multiple human CYP isoforms including CYP2C8 (IC50 = 4.56 µM), 2C9 (IC50 = 1.52 µM), 2C19 (IC50 = 28.40 µM), and 3A4/5 (IC50 = 53 µM for midazolam and IC50 = 81.20 µM for testosterone), but not CYP1A2, 2A6, 2B6, 2D6, and 2E1. These results strongly support a high propensity for rhinacanthin-C as a perpetrator of clinical herb-drug interaction via inhibiting various influx and efflux drug transporters (i.e., P-gp, BCRP, OATP1B1, and OATP1B3) and CYP isoforms (i.e., CYP2C8, CYP2C9, and CYP2C19). Thus, the potential for significant pharmacokinetic herb-drug interaction should be addressed when herbal products containing rhinacanthin-C are to be used in conjunction with other prescription drugs.
Assuntos
Acanthaceae/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações Ervas-Drogas , Naftoquinonas/farmacologia , Medicamentos sob Prescrição/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Células HEK293 , Humanos , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Células Madin Darby de Rim Canino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Recombinantes/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismoRESUMO
Clazosentan is a selective endothelin A receptor antagonist in development for the prevention and treatment of vasospasm postsubarachnoid hemorrhage. It is a substrate of organic anion-transporting polypeptide 1B1/1B3 based on preclinical data. This randomized, double-blind, two-period, cross-over study investigated the pharmacokinetics, safety, and tolerability of an intravenous infusion of clazosentan (15 mg/hour for 3 hours) after the intravenous administration of placebo or rifampin (600 mg/100 mL in 30 minutes). A total of 14 healthy male participants were enrolled resulting in 13 completers. Clazosentan exposure was three to four times higher after organic anion-transporting polypeptide 1B1/1B3 inhibition, as reflected by the geometric mean ratio (90% confidence interval) of area under the plasma concentration-time curve from zero to infinity: 3.88 (3.24-4.65). Clearance and volume of distribution decreased to a similar extent. Elimination half-life was not affected. A similar pattern but a higher incidence and frequency of adverse events were observed when clazosentan was given with rifampin than with placebo.
Assuntos
Dioxanos/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Rifampina/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Sulfonamidas/farmacocinética , Tetrazóis/farmacocinética , Adulto , Dioxanos/efeitos adversos , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Sulfonamidas/efeitos adversos , Tetrazóis/efeitos adversosRESUMO
ShenMai, an intravenous injection prepared from steamed Panax ginseng roots (Hongshen) and Ophiopogon japonicus roots (Maidong), is used as an add-on therapy for coronary artery disease and cancer; saponins are its bioactive constituents. Since many saponins inhibit human organic anion-transporting polypeptides (OATP)1B, this investigation determined the inhibition potencies of circulating ShenMai saponins on the transporters and the joint potential of these compounds for ShenMai-drug interaction. Circulating saponins and their pharmacokinetics were characterized in rats receiving a 30-min infusion of ShenMai at 10 mL/kg. Inhibition of human OATP1B1/1B3 and rat Oatp1b2 by the individual saponins was investigated in vitro; the compounds' joint inhibition was also assessed in vitro and the data was processed using the Chou-Talalay method. Plasma protein binding was assessed by equilibrium dialysis. Altogether, 49 saponins in ShenMai were characterized and graded into: 10-100 µmol/day (compound doses from ShenMai; 7 compounds), 1-10 µmol/day (17 compounds), and <1 µmol/day (25 compounds, including Maidong ophiopogonins). After dosing, circulating saponins were protopanaxadiol-type ginsenosides Rb1, Rb2, Rc, Rd, Ra1, Rg3, Ra2, and Ra3, protopanaxatriol-type ginsenosides Rg1, Re, Rg2, and Rf, and ginsenoside Ro. The protopanaxadiol-type ginsenosides exhibited maximum plasma concentrations of 2.1-46.6 µmol/L, plasma unbound fractions of 0.4-1.0% and terminal half-lives of 15.6-28.5 h (ginsenoside Rg3, 1.9 h), while the other ginsenosides exhibited 0.1-7.7 µmol/L, 20.8-99.2%, and 0.2-0.5 h, respectively. The protopanaxadiol-type ginsenosides, ginsenosides without any sugar attachment at C-20 (except ginsenoside Rf), and ginsenoside Ro inhibited OATP1B3 more potently (IC50, 0.2-3.5 µmol/L) than the other ginsenosides (≥22.6 µmol/L). Inhibition of OATP1B1 by ginsenosides was less potent than OATP1B3 inhibition. Ginsenosides Rb1, Rb2, Rc, Rd, Ro, Ra1, Re, and Rg2 likely contribute the major part of OATP1B3-mediated ShenMai-drug interaction potential, in an additive and time-related manner.
Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Ginsenosídeos/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Administração Intravenosa , Animais , Combinação de Medicamentos , Interações Medicamentosas , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Ginsenosídeos/administração & dosagem , Ginsenosídeos/sangue , Ginsenosídeos/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Ophiopogon/química , Panax/química , Ligação Proteica , Ratos Sprague-Dawley , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismoRESUMO
Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechanisms and clinical relevance of these interactions were characterized based on information from new drug application reviews. CYP3A inhibition and induction explained most of the observed drug interactions (new drugs as victims or as perpetrators), and transporters mediated about half of all DDIs, alone or with enzymes. Organic anion transporting polypeptide (OATP)1B1/1B3 played a significant role, mediating more than half of the drug interactions with area under the time-plasma curve (AUC) changes ≥5-fold. As victims, five new drugs were identified as sensitive substrates: abemeciclib, midostaurin, and neratinib for CYP3A and glecaprevir and voxilaprevir for OATP1B1/1B3. As perpetrators, three drugs were considered strong inhibitors: ribociclib for CYP3A, glecaprevir/pibrentasvir for OATP1B1/1B3, and sofosbuvir/velpatasvir/voxilaprevir for OATP1B1/1B3 and breast cancer resistance protein. No strong inducer of enzymes or transporters was identified. DDIs with AUC changes ≥5-fold and almost all DDIs with AUC changes 2- to 5-fold had dose recommendations in their respective drug labels. A small fraction of DDIs with exposure changes <2-fold had a labeling impact, mostly related to drugs with narrow therapeutic indices. As with drugs approved in recent years, all drugs found to be sensitive substrates or strong inhibitors of enzymes or transporters were among oncology or antiviral treatments, suggesting a serious risk of DDIs in these patient populations for whom effective therapy is already complex because of polytherapy.
Assuntos
Área Sob a Curva , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Aprovação de Drogas , Quimioterapia Combinada/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Neoplasias/tratamento farmacológico , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Estados Unidos , United States Food and Drug Administration , Viroses/tratamento farmacológicoRESUMO
GDC-0810 was under development as an oral anti-cancer drug for the treatment of estrogen receptor-positive breast cancer as a single agent or in combination. In vitro data indicated that GDC-0810 is a potent inhibitor of OATP1B1/1B3. To assess clinical risk, a PBPK model was developed to predict the transporter drug-drug interaction (tDDI) between GDC-0810 and pravastatin in human. The PBPK model was constructed in Simcyp® by integrating in vitro and in vivo data for GDC-0810. The prediction of human pharmacokinetics (PK) was verified using GDC-0810 phase I clinical PK data. The Simcyp transporter DDI model was verified using known OATP1B1/1B3 inhibitors (rifampicin, cyclosporine and gemfibrozil) and substrate (pravastatin), prior to using the model to predict GDC-0810 tDDI. The effect of GDC-0810 on pravastatin PK was then predicted based on the proposed clinical scenarios. Sensitivity analysis was conducted on the parameters with uncertainty. The developed PBPK model described the PK profile of GDC-0810 reasonably well. In the tDDI verification, the model reasonably predicted pravastatin tDDI caused by rifampicin and gemfibrozil OATP1B1/3 inhibition but under-predicted tDDI caused by cyclosporine. The effect of GDC-0810 on pravastatin PK was predicted to be low to moderate (pravastatin Cmax ratios 1.01-2.05 and AUC ratio 1.04-2.23). The observed tDDI (Cmax ratio 1.20 and AUC ratio 1.41) was within the range of the predicted values. This work demonstrates an approach using a PBPK model to prospectively assess tDDI caused by a new chemical entity as an OATP1B1/3 uptake transporter inhibitor to assess clinical risk and to support development strategy.
Assuntos
Cinamatos/farmacologia , Indazóis/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Modelos Biológicos , Pravastatina/farmacocinética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Área Sob a Curva , Ciclosporina/farmacologia , Interações Medicamentosas , Genfibrozila/farmacologia , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Rifampina/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismoRESUMO
The aim of the present study was to establish a physiologically based pharmacokinetic (PBPK) model for coproporphyrin I (CP-I), a biomarker supporting the prediction of drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1B (OATP1B), using clinical DDI data with an OATP1B inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP1Bs (Ki,u,OATP1Bs ) and multidrug resistance-associated protein two-mediated biliary excretion were estimated as 0.23 and 0.87 µM, respectively, from previous reports. Sensitivity analysis demonstrated that the Ki,u,OATP1Bs and biosynthesis rate of CP-I affected the magnitude of the interaction. Ki,u,OATP1Bs values optimized by nonlinear least-squares fitting were ~0.5-fold of the initial value. It was determined that the blood concentration-time profiles of four statins were well-predicted using corrected individual Ki,u,OATP1B values (ratio of in vitro Ki,u(statin) /in vitro Ki,u(CP-I) ). In conclusion, PBPK modeling of CP-I supports dynamic prediction of OATP1B-mediated DDIs.
Assuntos
Coproporfirinas/farmacologia , Coproporfirinas/farmacocinética , Interações Medicamentosas , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Fígado/metabolismo , Modelos Biológicos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/metabolismo , Coproporfirinas/sangue , HumanosRESUMO
In a recent study, limited to South Asian Indian subjects (n = 12), coproporphyrin (CP) I and CPIII demonstrated properties appropriate for an organic anion-transporting polypeptide (OATP) 1B endogenous probe. The current studies were conducted in healthy volunteers of mixed ethnicities, including black, white, and Hispanic subjects, to better understand the utility of these biomarkers in broader populations. After oral administration with 600 mg rifampin, AUC(0-24h) values were 2.8-, 3.7-, and 3.6-fold higher than predose levels for CPI and 2.6-, 3.1-, and 2.4-fold higher for CPIII, for the three populations, respectively. These changes in response to rifampin were consistent with previous results. The sensitivity toward OATP1B inhibition was also investigated by evaluating changes of plasma CP levels in the presence of diltiazem and itraconazole [administered as part of an unrelated drug-drug interaction (DDI) investigation], two compounds that were predicted to have minimal inhibitory effect on OATP1B. Administration of diltiazem and itraconazole did not increase plasma CPI and CPIII concentrations relative to prestudy levels, in agreement with predictions from in vitro parameters. Additionally, the basal CP concentrations in subjects with SLCO1B1 c.521TT genotype were comparable to those with SLCO1B1 c.521TC genotype, similar to studies with probe substrates. However, subjects with SLCO1B1 c.388AG and c.388GG genotypes (i.e., increased OATP1B1 transport activity for certain substrates) had lower concentrations of CPI than those with SLCO1B1 c.388AA. Collectively, these findings provide further evidence supporting the translational value of CPI and CPIII as suitable endogenous clinical probes to gauge OATP1B activity and potential for OATP1B-mediated DDIs.
Assuntos
Transporte Biológico/fisiologia , Biomarcadores/metabolismo , Coproporfirinas/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Adulto , Transporte Biológico/efeitos dos fármacos , Coproporfirinas/genética , Interações Medicamentosas/fisiologia , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/genética , Rifampina/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Adulto JovemRESUMO
INTRODUCTION: Coproporphyrin (CP) I and III have recently been proposed as endogenous clinical biomarkers to predict organic anion-transporting polypeptide 1B (OATP1B)-mediated drug-drug interactions (DDIs). In the present study, we first investigated the in vitro selectivity of CPI and CPIII towards drug uptake and efflux transporters. We then assessed the in vivo biomarker sensitivity towards OATP1B inhibition. METHODS: To assess transporter selectivity, incubations with CPI and CPIII were performed in vitro, using single transporter-expressing and control systems. Furthermore, CPI and CPIII plasma concentrations were determined from participants of three independent clinical trials who were administered with either a strong, moderate, or mild clinical OATP1B inhibitor. RESULTS: Our results show that CPI and CPIII are substrates of OATP1B1, OATP1B3, the multidrug resistance-associated protein (MRP) 2, and MRP3. No substrate interaction was shown for other prominent drug transporters that have been associated with clinical DDIs. Results from clinical studies demonstrated that changes in CPI and CPIII plasma levels were predictive for moderate (two to threefold area under the concentration-time curve [AUC] increase) and strong (≥ fivefold increases) clinical OATP1B inhibition. Furthermore, CPI, but not CPIII, concentration changes were predictive for a mild clinically observed DDI where CPI AUC increases of 1.4-fold were comparable with those observed for pitavastatin as victim drug (AUC increases of 1.5-fold). CONCLUSION: Our results demonstrate the selectivity of CPI and CPIII towards the OATP1B/MRP pathway, and the herein reported data further underline the potential of CPI and CPIII as selective and sensitive clinical biomarkers to quantify OATP1B-mediated DDIs.