RESUMO
Background: Monitoring noncommunicable diseases is regarded as a critical concern that has to be managed in order to avoid a wide variety of complications such as increasing blood lipid levels known as dyslipidemia. Statin drugs, mostly, Rosuvastatin (RSV) was investigated for its effectiveness in treating dyslipidemia. However, reaching the most efficient treatment is essential and improving the effect of RSV is crucial. Therefore, a combination therapy was a good approach for achieving significant benefit. Although RSV is hydrophobic, which would affect its absorption and bioavailability following oral administration, overcoming this obstacle was important. Purpose: To that end, the purpose of the present investigation was to incorporate RSV into certain lipid-based nanocarriers, namely, nanostructured lipid carrier (NLC) prepared with virgin coconut oil (CCO). Methods: The optimized RSV-NLC formula was selected, characterized and examined for its in vitro, kinetic, and stability profiles. Eventually, the formula was investigated for its in vivo hypolipidemic action. Results: The optimized NLC formulation showed a suitable particle size (279.3±5.03 nm) with PDI 0.237 and displayed good entrapment efficiency (75.6±1.9%). Regarding in vitro release, it was efficiently prolonged for 24 h providing 93.7±1.47%. The optimized formula was established to be stable after 3 months storage at two different conditions; 4°C and 25°C. Importantly, including CCO in the development of RSV-NLC could impressively enhance lowering total cholesterol level in obese rat models, which endorse the potential synergistic action between RSV and CCO. Conclusion: The study could elucidate the impact of developing NLC using CCO for improving RSV anti-hyperlipidemic activity.
Assuntos
Óleo de Coco , Portadores de Fármacos , Hipolipemiantes , Nanoestruturas , Tamanho da Partícula , Rosuvastatina Cálcica , Animais , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacologia , Rosuvastatina Cálcica/administração & dosagem , Óleo de Coco/química , Óleo de Coco/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Hipolipemiantes/farmacocinética , Hipolipemiantes/administração & dosagem , Portadores de Fármacos/química , Masculino , Ratos , Nanoestruturas/química , Lipídeos/química , Lipídeos/sangue , Ratos Wistar , Liberação Controlada de Fármacos , Disponibilidade Biológica , Administração OralRESUMO
The prevalence of metabolic dysfunction associated-steatotic liver disease (MASLD) (formerly known as nonalcoholic fatty liver disease; NAFLD) is estimated at around 32% of the world's population, resulting in a major healthcare concern in recent times. Current pharmaceutical methods lack efficacy for the treatment of the disease because of suboptimal pharmacokinetic parameters including poor bioavailability, short half-life, and premature clearance. Designing an efficient drug delivery system that provides a protective environment is critical for addressing these challenges. Such a system should aim to enhance the cellular uptake of drugs, improve their bioavailability, and reduce the chances of rapid clearance. Here, we developed nanoengineered natural cell membrane-derived nanoparticles (CMNs) incorporated with a model drug, rosuvastatin, in the bilayer assembly of CMNs to reduce the accumulation of lipids in hepatocytes, a hallmark of MASLD. We used a cell extrusion technique to develop self-assembled CMNs with precise size control compared to the cell shearing method. Interestingly, the prepared CMNs were found to be nonphagocytic, representing around 1.13% of phosphatidylserine receptors on healthy cells, which allows the possibility of their use as stealth nanoparticles for drug delivery. Furthermore, CMNs exhibit higher drug-loading efficiency, excellent cytocompatibility, and enhanced cellular internalization capabilities. Moreover, we show that the delivery of rosuvastatin-loaded CMNs in the in vitro MASLD model efficiently reduced hepatocyte lipid accumulation, including total cholesterol (26.8 ± 3.1%) and triglycerides (11.8 ± 0.8%), compared to the negative control. Taken together, the nanoengineered biomimetic CMNs enhance the drug's bioactivity in hepatic cells, establishing a foundation for further investigation of this drug delivery system in treating MASLD.
Assuntos
Materiais Biomiméticos , Membrana Celular , Nanopartículas , Hepatopatia Gordurosa não Alcoólica , Rosuvastatina Cálcica , Humanos , Nanopartículas/química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacologia , Rosuvastatina Cálcica/farmacocinética , Membrana Celular/metabolismo , Membrana Celular/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Sistemas de Liberação de MedicamentosRESUMO
Mesoporous silica nanoparticles (MSNPs) coated by chitosan (CS) were shown to be a proper candidate as a carrier for drug delivery purposes. However, choosing the suitable drug-containing complexes to be applied on MSNPs-CS is of much greater importance to evaluate the possible candidate for an efficient combination of cell viability, drug release kinetics, and atherosclerosis prevention. In this regard, this study concentrates on the synthesis and assessment of coated MSNPs-CS designed for drug delivery purposes. The MSNPs are coated with polyelectrolyte complexes (PEC) composed of CS and dextran sulfate (MSNPs-CS-DX), serving as a versatile drug carrier with favorable biological characteristics. CS-DX is applied to MSNPs without requiring complex or multi-step synthesis procedures. Rosuvastatin, a cholesterol-lowering medication, is chosen for its therapeutic relevance. Additionally, CS-DX is found to relatively impede the uptake of low-density lipoproteins (LDLs) by macrophages, enhancing their potential therapeutic utility. FTIR pattern, FESEM, and TEM images prove MSNPs-CS-DX formation. DLS measurement demonstrates the average particle size of 110 nm for MSNPs, with the combined thickness of CS and DX layers ranging from 10 to 15 nm. BET test is carried out to evaluate the pore size and porosity of structure, showing outstanding results that cause an entrapment efficiency of 57% for MSNPs-CS-DX. Furthermore, the findings demonstrate the pH sensitivity of MSNPs-CS-DX on drug release kinetics. Notably, the CS-DX layer exhibits a significant enhancement in cell viability of human umbilical vein endothelial cells (HUVEC) by approximately 24% within a 24 h timeframe compared to MSNPs lacking CS-DX.
Assuntos
Quitosana , Sulfato de Dextrana , Sistemas de Liberação de Medicamentos , Dióxido de Silício , Quitosana/química , Dióxido de Silício/química , Concentração de Íons de Hidrogênio , Sulfato de Dextrana/química , Porosidade , Humanos , Portadores de Fármacos/química , Nanopartículas/química , Tamanho da Partícula , Liberação Controlada de Fármacos , Sobrevivência Celular/efeitos dos fármacos , Animais , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/farmacologia , Camundongos , Materiais Revestidos Biocompatíveis/química , Lipoproteínas LDL , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Células RAW 264.7RESUMO
INTRODUCTION: In addition to the well-established understanding of the pharmacogenetics of drug-metabolizing enzymes, there is growing data on the effects of genetic variation in drug transporters, particularly ATP-binding cassette (ABC) transporters. However, the evidence that these genetic variants can be used to predict drug effects and to adjust individual dosing to avoid adverse events is still limited. AREAS COVERED: This review presents a summary of the current literature from the PubMed database as of February 2024 regarding the impact of genetic variants on ABCG2 function and their relevance to the clinical use of the HMG-CoA reductase inhibitor rosuvastatin and the xanthine oxidase inhibitor allopurinol. EXPERT OPINION: Although there are pharmacogenetic guidelines for the ABCG2 missense variant Q141K, there is still some conflicting data regarding the clinical benefits of these recommendations. Some caution appears to be warranted in homozygous ABCG2 Q141K carriers when rosuvastatin is administered at higher doses and such information is already included in the drug label. The benefit of dose adaption to lower possible side effects needs to be evaluated in prospective clinical studies.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Alopurinol , Inibidores de Hidroximetilglutaril-CoA Redutases , Proteínas de Neoplasias , Farmacogenética , Rosuvastatina Cálcica , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Alopurinol/farmacocinética , Alopurinol/administração & dosagem , Alopurinol/farmacologia , Polimorfismo Genético , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Animais , Mutação de Sentido IncorretoRESUMO
Pritelivir is a novel viral helicase-primase inhibitor active against herpes simplex virus. In vitro drug-drug interaction studies indicated that pritelivir has the potential for clinically relevant interactions on the cytochrome P450 (CYP) enzymes 2C8, 2C9, 3A4, and 2B6, and intestinal uptake transporter organic anion transporting polypeptide (OATP) 2B1 and efflux transporter breast cancer resistance protein (BCRP). This was evaluated in 2 clinical trials. In 1 trial the substrates flurbiprofen (CYP2C9), bupropion (CYP2B6), and midazolam (CYP3A4) were administered simultaneously as part of the Geneva cocktail, while the substrate celiprolol (OAPT2B1) was administered separately. In another trial, the substrates repaglinide (CYP2C8) and rosuvastatin (BCRP) were administered separately. Exposure parameters of the substrates and their metabolites (flurbiprofen and bupropion only) were compared after administration with or without pritelivir under therapeutic concentrations. The results of these trials indicated that pritelivir has no clinically relevant effect on the exposure of substrates for the intestinal uptake transporter OATP2B1 and the CYP enzymes 3A4, 2B6, 2C9, and 2C8, and has a weak inhibitory effect on the intestinal efflux transporter BCRP. In summary, the results suggest that pritelivir has a low drug-drug interaction potential.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Sistema Enzimático do Citocromo P-450 , Interações Medicamentosas , Humanos , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Feminino , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Masculino , Adulto , Bupropiona/farmacologia , Bupropiona/farmacocinética , Sulfonamidas/farmacologia , Pessoa de Meia-Idade , Rosuvastatina Cálcica/farmacologia , Rosuvastatina Cálcica/farmacocinética , Flurbiprofeno/farmacologia , Flurbiprofeno/farmacocinética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Carbamatos/farmacologia , Midazolam/farmacocinética , Midazolam/farmacologia , Adulto Jovem , Piperidinas/farmacologia , Piperidinas/farmacocinéticaRESUMO
Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1-/-, Abcb1a/1b;Abcg2-/- and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2-/- << Slco1a/1b/2b1-/- < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2-/- or Slco1a/1b/2b1-/- mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Bilirrubina , Camundongos Knockout , Transportadores de Ânions Orgânicos , Animais , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Bilirrubina/sangue , Bilirrubina/metabolismo , Camundongos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Terfenadina/farmacocinética , Terfenadina/análogos & derivados , Masculino , Transporte Biológico , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/farmacologia , Camundongos Endogâmicos C57BLRESUMO
Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.
Assuntos
Benzamidas , Citocromo P-450 CYP3A , Pirimidinas , Ritonavir , Adulto , Humanos , Citocromo P-450 CYP3A/metabolismo , Rifampina/farmacologia , Midazolam/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Rosuvastatina Cálcica/farmacocinética , Proteínas de Neoplasias/metabolismo , Interações Medicamentosas , Proteínas de Membrana Transportadoras/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI. METHODS: DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days - 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m2 initial dose, then 250 mg/m2 QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods. RESULTS: Bupropion exposure was not increased, whereas rosuvastatin Cmax and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib. CONCLUSION: The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03864042, registered 6 March 2019.
Assuntos
Bupropiona , Carbamatos , Coproporfirinas , Interações Medicamentosas , Inibidores de Hidroximetilglutaril-CoA Redutases , Rosuvastatina Cálcica , Sulfonamidas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Bupropiona/administração & dosagem , Bupropiona/farmacocinética , Carbamatos/administração & dosagem , Carbamatos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Idoso de 80 Anos ou maisRESUMO
Ticagrelor and rosuvastatin are often used concomitantly after atherothrombotic events. Several cases of rhabdomyolysis during concomitant ticagrelor and rosuvastatin have been reported, suggesting a drug-drug interaction. We showed recently that ticagrelor inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1-mediated rosuvastatin transport in vitro. The aim of this study was to investigate the effects of ticagrelor on rosuvastatin pharmacokinetics in humans. In a randomized, crossover study, 9 healthy volunteers ingested a single dose of 90 mg ticagrelor or placebo, followed by a single 10 mg dose of rosuvastatin 1 hour later. Ticagrelor 90 mg or placebo were additionally administered 12, 24, and 36 hours after their first dose. Ticagrelor increased rosuvastatin area under the plasma concentration-time curve (AUC) and peak plasma concentration 2.6-fold (90% confidence intervals: 1.8-3.8 and 1.7-4.0, P = 0.001 and P = 0.003), and prolonged its half-life from 3.1 to 6.6 hours (P = 0.009). Ticagrelor also decreased the renal clearance of rosuvastatin by 11% (3%-19%, P = 0.032). The N-desmethylrosuvastatin:rosuvastatin AUC0-10h ratio remained unaffected by ticagrelor. Ticagrelor had no effect on the plasma concentrations of the endogenous OATP1B substrates glycodeoxycholate 3-O-glucuronide, glycochenodeoxycholate 3-O-glucuronide, glycodeoxycholate 3-O-sulfate, and glycochenodeoxycholate 3-O-sulfate, or the sodium-taurocholate cotransporting polypeptide substrate taurocholic acid. These data indicate that ticagrelor increases rosuvastatin concentrations more than twofold in humans, probably mainly by inhibiting intestinal BCRP. Because the risk for rosuvastatin-induced myotoxicity increases along with rosuvastatin plasma concentrations, using ticagrelor concomitantly with high doses of rosuvastatin should be avoided.
Assuntos
Neoplasias da Mama , Glucuronídeos , Humanos , Feminino , Rosuvastatina Cálcica/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ticagrelor , Estudos Cross-Over , Ácido Glicoquenodesoxicólico , Proteínas de Neoplasias/metabolismo , Interações Medicamentosas , Sulfatos/metabolismoRESUMO
Lasmiditan is an in vitro inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically based pharmacokinetic models of lasmiditan, and assess the safety and tolerability of rosuvastatin and dabigatran co-administered with lasmiditan. In this open-label, post-marketing drug-drug interaction, phase 1 clinical trial, eligible participants were adults aged 21-70 years with a body mass index of 18.5-35.0 kg/m2 . Part 1 (P-gp, 150 mg dabigatran etexilate with 200 mg lasmiditan) and part 2 (BCRP, 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: a single dose of probe substrate administered on day -2 with pharmacokinetic evaluation; 1-week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co-administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty-six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co-administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least-squares (LS) mean ratios of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞ ) and maximum observed drug concentration (Cmax ) were not contained within the non-effect boundaries (0.80 to 1.25). Dabigatran AUC0-∞ increased by 25% and Cmax increased by 22%. The median time of maximum observed drug concentration (tmax ) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co-administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC0-∞ and Cmax were contained within non-effect boundaries (0.80-1.25). Rosuvastatin AUC0-∞ increased by 15% and Cmax increased by 7%. The median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P-gp substrates and no clinically relevant effect on BCRP substrates.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Neoplasias da Mama , Adulto , Feminino , Humanos , Área Sob a Curva , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Estudos Cross-Over , Dabigatrana , Interações Medicamentosas , Proteínas de Neoplasias , Rosuvastatina Cálcica/farmacocinética , Adulto Jovem , Pessoa de Meia-Idade , IdosoRESUMO
Evaluating Drug-Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady-state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4-component transporter cocktail. This open-label, non-randomized, 2-period fixed-sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18-55 years with body mass index 18.5-29.9 kg/m2 . During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞ ) and the maximum measured concentration of the analyte in plasma (Cmax ), and the secondary endpoint was the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz ). Steady-state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (-2% to -9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE-1/MATE-2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0-∞ /Cmax /AUC0-tz ) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug-transporter interactions in vivo.
Assuntos
Metformina , Humanos , Metformina/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Furosemida/metabolismo , Furosemida/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Digoxina , Voluntários Saudáveis , Proteínas de Neoplasias/metabolismo , Tretinoína/metabolismoRESUMO
PURPOSE: Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. METHODS: In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. RESULTS: In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by ~ 13% and maximum concentration (Cmax) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration. CONCLUSION: Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.
Assuntos
Proteínas de Neoplasias , Transportadores de Ânions Orgânicos , Adulto , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Biomarcadores , Interações Medicamentosas , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/farmacologiaRESUMO
Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can assess hepatic extraction, clearance, biliary excretion, and drug-drug interaction (DDI). Eleven livers were included in the study, seven with a cirrhotic and four with a noncirrhotic disease background. After explantation of the diseased liver, NMP was initiated. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin, and furosemide; OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with perpetrator drugs to study relevant DDIs. The explanted livers showed good viability and functionality during 360 minutes of NMP. Hepatic extraction ratios close to in vivo reported values were measured. Hepatic clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in maximum plasma concentration (Cmax ) of 11.50 and 2.89 times, respectively, compared with noncirrhotic livers. No major differences were observed for metformin and furosemide. Interaction of rosuvastatin or digoxin with perpetrator drugs were more pronounced in noncirrhotic livers compared with cirrhotic livers. Our results demonstrated that NMP of human diseased explanted livers is an excellent model to assess hepatic extraction, clearance, biliary excretion, and DDI. Gaining insight into pharmacokinetic profiles of OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds is a first step toward studying transporter functions in diseased livers.
Assuntos
Furosemida , Metformina , Humanos , Rosuvastatina Cálcica/farmacocinética , Furosemida/farmacocinética , Eliminação Hepatobiliar , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Fígado/metabolismo , Cirrose Hepática , Metformina/farmacocinética , Digoxina/farmacocinética , Interações MedicamentosasRESUMO
Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates.
Assuntos
COVID-19 , Metformina , Transportadores de Ânions Orgânicos , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , SARS-CoV-2 , Rosuvastatina Cálcica/farmacocinética , Inibidores de Proteases , Proteínas de Neoplasias/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Interações Medicamentosas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Digoxina/farmacocinética , Inibidores Enzimáticos , Transportador 1 de Cátions Orgânicos , Metformina/farmacocinética , Transporte Biológico , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismoRESUMO
We present 3 patients diagnosed with rhabdomyolysis 1-6 months after the initiation of concomitant rosuvastatin and ticagrelor medication. A literature review and Food and Drug Administration adverse event reporting system revealed >40 reports of rhabdomyolysis during concomitant ticagrelor and rosuvastatin, including 3 with a fatal outcome. We show that ticagrelor inhibits breast cancer resistance protein-, organic anion transporting polypeptide (OATP) 1B1-, 1B3- and 2B1-mediated transport of rosuvastatin in vitro with half-maximal unbound inhibitory concentrations of 0.36, 4.13, 7.5 and 3.26 µM, respectively. A static drug interaction model predicted that ticagrelor may inhibit intestinal breast cancer resistance protein and thus increase rosuvastatin plasma exposure 2.1-fold, whereas the OATP-mediated hepatic uptake of rosuvastatin should not be inhibited due to relatively low portal ticagrelor concentrations. Taken together, concomitant use of ticagrelor with rosuvastatin may increase the systemic exposure to rosuvastatin and the risk of rosuvastatin-induced rhabdomyolysis. Further studies are warranted to investigate the potential pharmacokinetic interaction between ticagrelor and rosuvastatin in humans.
Assuntos
Neoplasias da Mama , Transportadores de Ânions Orgânicos , Rabdomiólise , Estados Unidos , Humanos , Feminino , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacocinética , Ticagrelor/efeitos adversos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Proteínas de Neoplasias/metabolismo , Interações Medicamentosas , Transportadores de Ânions Orgânicos/metabolismo , Rabdomiólise/induzido quimicamente , Neoplasias da Mama/tratamento farmacológicoRESUMO
Statins are among the most commonly prescribed medications worldwide. Rosuvastatin is a moderate- to high-intensity statin depending on the prescribed dose. Statin-associated muscle symptoms are the main side effects, contributing to low adherence to statins. The missense variant rs2231142 in ABCG2 affects the functionality of the ABCG2 transporter, altering the pharmacokinetics and pharmacodynamics of rosuvastatin. This special report aims to accentuate the importance of considering the ABCG2 genotype upon prescribing rosuvastatin in high cardiovascular disease risk subgroups, specifically Native Hawaiian and Pacific Islander populations. Based on the reported frequencies of rs2231142 in ABCG2, it may be justifiable to initiate low-dose rosuvastatin in Samoans relative to Marshallese or Native Hawaiians. Interpopulation differences in pharmacogenetic allele frequencies underscore the need to disaggregate broad population categories to achieve health equity in treatment outcomes.
Rosuvastatin is a medication that is used to decrease levels of bad cholesterol in the blood. One of the side effects of rosuvastatin is muscle aches, which can cause patients to stop taking their medication. ABCG2 is a gene responsible for encoding ABCG2, an important transporter that plays a role in how the body interacts with many medications, including rosuvastatin. Genetic variations in ABCG2 result in a functional or nonfunctional transporter. This special report aims to focus on the importance of considering genetic variations in ABCG2 among different population subgroups, in particular Native Hawaiians, Samoans and Marshallese. The ABCG2 genotype could inform clinicians about the most effective rosuvastatin dose to prescribe. This approach highlights the importance of individualized patient characteristics above and beyond race and ethnicity.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Inibidores de Hidroximetilglutaril-CoA Redutases , Rosuvastatina Cálcica , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacocinéticaRESUMO
Vatiquinone is a small-molecule inhibitor of 15-lipoxygenase in phase 3 development for patients with mitochondrial disease and Friedreich ataxia. The objective of this analysis was to determine the effect of vatiquinone on the pharmacokinetic profile of rosuvastatin, a breast cancer resistance protein substrate. In vitro investigations demonstrated potential inhibition of BCRP by vatiquinone (half maximal inhibitory concentration, 3.8 µM). An open-label, fixed-sequence drug-drug interaction study in healthy volunteers was conducted to determine the clinical relevance of this finding. Subjects received a single dose of 20-mg rosuvastatin followed by a 7-day washout. On days 8 through 14, subjects received 400 mg of vatiquinone 3 times daily. On day 12, subjects concomitantly received a single dose of 20-mg rosuvastatin. The geometric mean ratio for maximum plasma concentration was 77.8%; however, the rosuvastatin disposition phase appeared unaffected. The geometric mean ratios for the area under the plasma concentration-time curve from time 0 to time t and from time 0 to infinity were 103.2% and 99.9%, respectively. Mean rosuvastatin apparent elimination half-life was similar between treatment groups. These results demonstrate that vatiquinone has no clinically relevant effect on the pharmacokinetics of rosuvastatin.
Assuntos
Neoplasias da Mama , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Feminino , Rosuvastatina Cálcica/farmacocinética , Inibidores de Lipoxigenase , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Araquidonato 15-Lipoxigenase/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Proteínas de Neoplasias/metabolismo , Interações MedicamentosasRESUMO
AIMS: The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin. METHODS: We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88). RESULTS: In a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10-12 and P = 3.2 × 10-15 ). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P = 4.69 × 10-5 ) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16-62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P = 2.6 × 10-4 ) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P = .01). CONCLUSION: These data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.
Assuntos
Estudo de Associação Genômica Ampla , Transportadores de Ânions Orgânicos , Rosuvastatina Cálcica/farmacocinética , Testes Farmacogenômicos , Estudos Prospectivos , Polimorfismo de Nucleotídeo Único , Genótipo , Transportadores de Ânions Orgânicos/genéticaRESUMO
This study evaluates the influence of pregnancy and HIV infection in conjunction with the use of raltegravir, lamivudine, and tenofovir disoproxil fumarate (combined antiretroviral therapy [cART]) on intestinal P-glycoprotein (P-gp) and hepatic organic anion transporter polypeptide (OATP) 1B1/1B3 and/or breast cancer resistance protein (BCRP) drug transporter activity using rosuvastatin (OATP1B/BCRP) and fexofenadine (P-gp) probes. Single oral doses of 5-mg rosuvastatin and 60-mg fexofenadine were administered to women living with HIV under cART in the third trimester of gestation (n = 15) and postpartum period (n = 10). A control group of 12 healthy nonpregnant women also was investigated. Pharmacokinetic parameters were estimated by using a noncompartmental method and evaluated by t test (P < .05). The rosuvastatin area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last ) value was higher in the third trimester of pregnancy (19.5 [95%CI, 16.8-22.3] ng ⢠h/mL] when compared to postpartum (13.3 [95%CI, 9.3-17.5] ng ⢠h/mL), while the fexofenadine AUC0-last values did not differ between the third trimester of pregnancy (738.0 [95%CI, 611.4-864.6] ng ⢠h/mL) and postpartum period (874.9 [95%CI, 408.2-1342.0] ng⢠h/mL). The rosuvastatin AUC0-last values did not differ between healthy nonpregnant women (13.8 [95%CI, 10.0-17.6] ng ⢠h/mL) and women living with HIV in the postpartum period (13.3 [95%CI, 9.3-17.5] ng ⢠h/mL), and the fexofenadine AUC0-last values did not differ between the 2 investigated groups (603.6 [95%CI, 467.5-739.7] ng ⢠h/mL vs 874.9 [95%CI, 408.2-1342.0] ng ⢠h/mL). It is suggested that gestation inhibits the hepatic OATP1B1/1B3 and/or BCRP activity but does not alter intestinal P-gp activity. The influence of HIV infection in conjunction with use of cART on OATP1B/BCRP and intestinal P-gp activity was not observed.
Assuntos
Neoplasias da Mama , Infecções por HIV , Transportadores de Ânions Orgânicos , Humanos , Feminino , Gravidez , Rosuvastatina Cálcica/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Gestantes , Infecções por HIV/tratamento farmacológico , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Interações Medicamentosas , Proteínas de Neoplasias/metabolismoRESUMO
This study was designed to assess the quantitative performance of endogenous biomarkers for organic anion transporting polypeptide (OATP) 1B1/1B3-mediated drug-drug interactions (DDIs). Ten healthy volunteers orally received OATP1B1/1B3 probe cocktail (0.2 mg pitavastatin, 1 mg rosuvastatin, and 2 mg valsartan) and an oral dose of cyclosporin A (CysA, 20 mg and 75 mg) separated by a 1-hour interval (20 mg (-1 hour), and 75 mg (-1 hour)). CysA 75 mg was also given with a 3-hour interval (75 mg (-3 hours)) to examine the persistence of OATP1B1/1B3 inhibition. The area under the plasma concentration-time curve ratios (AUCRs) were 1.63, 3.46, and 2.38 (pitavastatin), 1.39, 2.16, and 1.81 (rosuvastatin), and 1.42, 1.77, and 1.85 (valsartan), at 20 mg, 75 mg (-1 hour) and 75 mg (-3 hours) of CysA, respectively. CysA effect on OATP1B1/1B3 was unlikely to persist at the dose examined. Among 26 putative OATP1B1/1B3 biomarkers evaluated, AUCR and maximum concentration ratio (Cmax R) of CP-I showed the highest Pearson's correlation coefficient with CysA AUC (0.94 and 0.93, respectively). Correlation between AUCR of pitavastatin, and Cmax R or AUCR of CP-I were consistent between this study and our previous study using rifampicin as an OATP1B1/1B3 inhibitor. Nonlinear regression analysis of AUCR-1 of pitavastatin and CP-I against CysA Cmax yielded Ki,OATP1B1/1B3,app (109 ± 35 and 176 ± 42 nM, respectively), similar to the Ki ,OATP1B1/1B3 estimated by our physiologically-based pharmacokinetic model analysis described previously (107 nM). The endogenous OATP1B1/1B3 biomarkers, particularly Cmax R and AUCR of CP-I, corroborates OATP1B1/1B3 inhibition and yields valuable information that improve accurate DDI predictions in drug development, and enhance our understanding of interindividual variability in the magnitude of DDIs.