RESUMO
We previously reported that repeated oral administration of vonoprazan (VPZ) followed by oral administration of proguanil (PG) in healthy adults increased blood concentration of PG and decreased blood concentration of its metabolite cycloguanil (CG) compared with administration of PG alone. In this study, we investigated whether this interaction can be quantitatively explained by VPZ inhibition of PG metabolism. In an in vitro study using human liver microsomes, VPZ inhibited CG formation from PG in a concentration-dependent manner, and the inhibition was enhanced depending on preincubation time. Then, a physiologically based pharmacokinetic (PBPK) model analysis was performed incorporating the obtained inhibition parameters. By fitting the blood concentration profiles of VPZ and PG/CG after VPZ and PG were orally administered alone to our PBPK model, parameters were obtained which can reproduce their concentration profiles. In contrast, when the VPZ inhibition parameters for CG formation from the in vitro study were incorporated, the predicted blood PG and CG concentrations were unchanged; the apparent dissociation constant had to be set to about 1/23 of the obtained in vitro value to reproduce the observed interaction. Further comprehensive evaluation is required, including the possibility that mechanisms other than metabolic inhibition may be involved.
Assuntos
Proguanil , Pirróis , Sulfonamidas , Triazinas , Adulto , Humanos , Proguanil/farmacocinética , Ativação Metabólica , Pirróis/farmacologiaRESUMO
When NA808, a potent HCV replication inhibitor, was intravenously administered to rats, it was distributed to the liver. The AUC ratio in the liver of 20 mg/kg to 2 mg/kg was greater than the dose ratio, whereas exposure in plasma was increased in a dose-proportional manner. Saturation of biliary excretion was also shown at 20 mg/kg.NA808 was revealed to be a substrate for both OATP1B and MRP2 transporters by an in vitro study using OATP1B1-MRP2 expressing cells. [14C]NA808 was taken up into the cells by OATP1B1 and excreted from cells by MRP2 efficiently (Papp ratio: 24.2-70.2). The Papp ratio decreased with increasing NA808 concentration.PBPK modelling was constructed to display the blood and liver concentration time profile and biliary excretion of NA808. This model analysis was able to reproduce the pharmacokinetics in rats; the degree of increase in the liver exposure from 2 to 20 mg/kg was more than dose-proportional and was greater than the increase in the blood exposure due to saturation of efflux transporters.In drug development, to avoid unexpected toxicity in tissues, it is important to consider the potential for tissue non-linearity with linear plasma exposure based on pre-clinical data and PBPK modelling.
Assuntos
Citratos , Fígado , Ratos , Animais , Fígado/metabolismo , Citratos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Transporte BiológicoRESUMO
In vitro potency is one of the important parameters representing efficacy potential of drugs and commonly used as benchmark of efficacious exposure at early clinical development. There are limited numbers of studies which systematically investigate on how predictive in vitro potency is to estimate therapeutic drug exposure, especially those focusing on targeted anticancer agents despite the recent increase in approvals. This study aims to fill in such knowledge gaps. A total of 87 small molecule targeted drugs approved for oncology indication between 2001 and 2020 by the US Food and Drug Administration (FDA) were identified; relevant preclinical and clinical data were extracted from the public domain. Relationships between the in vitro potency and the therapeutic dose or exposure (unbound average drug concentration [Cu,av ] as the primary exposure metrics) were assessed by descriptive analyses. The Spearman's rank correlation test showed slightly better correlation of the Cu,av (ρ = 0.232, p = 0.041) rather than the daily dose (ρ = 0.186, p = 0.096) with the in vitro potency. Better correlation was observed for the drugs for hematologic malignancies compared with those for solid tumors (root mean square error: 140 [n = 28] versus 297 [n = 59]). The present study shows that in vitro potency is predictive to estimate the therapeutic drug exposure to some extent, whereas the general trend of overexposure was observed. The results suggested that in vitro potency alone is not sufficient and robust enough to estimate the clinically efficacious exposure of molecularly targeted small molecule oncology drugs. The totality of data, including both nonclinical and clinical, needs to be considered for dose optimization.
Assuntos
Antineoplásicos , Neoplasias , Estados Unidos , Humanos , United States Food and Drug Administration , Estudos Retrospectivos , Aprovação de Drogas , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Creatinine is a common biomarker of renal function and is secreted in the renal tubular cells via drug transporters, such as organic cation transporter 2 and multidrug and toxin extrusion (MATE) 1/2-K. To differentiate between drug-induced acute kidney injury (AKI) and drug interactions through the renal transporter, it has been examined whether these transporter inhibitions quantitatively explained increases in serum creatinine (SCr) at their clinically relevant concentrations using drugs without any changes in renal function. For such renal transporter inhibitors and recently approved tyrosine kinase inhibitors (TKIs), this mini-review describes clinical increases in SCr and inhibitory potentials against the renal transporters. Most cases of SCr elevations can be explained by considering the renal transporter inhibitions based on unbound maximum plasma concentrations, except for drugs associated with obvious changes in renal function. SCr increases for cobicistat, dolutegravir, and dronedarone, and some TKIs were significantly underestimated, and these underestimations were suggested to be associated with low plasma unbound fractions. Sensitivity analysis of SCr elevations regarding inhibitory potentials of MATE1/2-K demonstrated that typical inhibitors such as cimetidine, DX-619, pyrimethamine, and trimethoprim could give false interpretations of AKI according to the criteria based on relative or absolute levels of SCr elevations. Recent progress and current challenges of physiologically-based pharmacokinetics modeling for creatinine disposition were also summarized. Although it should be noted for the potential impact of in vitro assay designs on clinical translatability of transporter inhibitions data, mechanistic approaches could support decision-making in clinical development to differentiate between AKI and creatinine-drug interactions. SIGNIFICANCE STATEMENT: Serum creatinine (SCr) is widely used as an indicator of kidney function, but it increases due to inhibitions of renal transporters, such as multidrug and toxin extrusion protein 1/2-K despite no functional changes in the kidney. Such SCr elevations were quantitatively explained by renal transporter inhibitions except for some drugs with high protein binding. The present analysis demonstrated that clinically relevant inhibitors of the renal transporters could cause SCr elevations above levels corresponding to acute kidney injury criteria.
Assuntos
Injúria Renal Aguda , Proteínas de Transporte de Cátions Orgânicos , Humanos , Creatinina , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Rim/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Transporte Biológico , Injúria Renal Aguda/induzido quimicamenteRESUMO
BACKGROUND: Caffeine consumption is a risk factor for chronic daily headache but few studies have addressed relationships between pediatric patient caffeine levels and headache severity. We examined associations between serum and urine caffeine levels and headache severity in childhood and adolescent migraine cases. METHODS: Levels of caffeine and caffeine metabolites in serum and urine samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The Wilcoxon rank-sum test was used for comparisons of age, sleep time, headache severity, caffeine consumption, and caffeine detection. Spearman's rank correlation coefficient (ρ) was calculated for associations. Correlations where ρ ≥ 0.3 and differences where p < 0.05 were considered statistically significant. RESULTS: Of the 40 patients studied, 34 declared caffeine consumption and six declared no caffeine consumption. These two groups did not differ significantly in any of the above clinical parameters. Liquid chromatography-tandem mass spectrometry analysis of both serum and urine samples revealed nine caffeine-negative (level <0.0625 µM) and 31 caffeine-positive cases. The Headache Impact Test-6 (HIT-6) score was higher (p = 0.033) for the caffeine-positive group versus the caffeine-negative group. Caffeine was detected by LC-MS/MS in the serum and/or urine of three of the six patients who declared no caffeine consumption. No significant correlations were observed among age, sleep times, headache severity score, or levels of caffeine and caffeine metabolites. CONCLUSION: Thirty one of 40 (77.5%) cases of childhood/ adolescence migraine showed serum and urine caffeine positivity based on LC-MS/MS. The HIT-6 score, a measure of headache severity, was significantly higher for caffeine-positive versus caffeine-negative cases. Symptoms of childhood/adolescence migraine were exacerbated by caffeine consumption.
Assuntos
Transtornos de Enxaqueca , Espectrometria de Massas em Tandem , Humanos , Adolescente , Criança , Cromatografia Líquida , Transtornos de Enxaqueca/etiologia , Cafeína , Cefaleia , Fatores de RiscoRESUMO
Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean Cmax (144.3 ng/mL) and AUCinf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median tmax and mean t1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUCinf in Japanese subjects was within the range of AUCtau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients.
Assuntos
Etnicidade , Rilpivirina , Adulto , Povo Asiático , Voluntários Saudáveis , Humanos , Rilpivirina/efeitos adversos , População BrancaRESUMO
During new drug development, clinical drug interaction studies are carried out in accordance with the mechanism of potential drug interactions evaluated by in vitro studies. The obtained information should be provided efficiently to medical experts through package inserts and various information materials after the drug's launch. A recently updated Japanese guideline presents general procedures that are considered scientifically valid at the present moment. In this review, we aim to highlight the viewpoints of the Japanese guideline and enumerate drugs that were involved or are anticipated to be involved in evident pharmacokinetic drug interactions and classify them by their clearance pathway and potential intensity based on systematic reviews of the literature. The classification would be informative for designing clinical studies during the development stage, and the appropriate management of drug interactions in clinical practice.
Assuntos
Desenvolvimento de Medicamentos , Preparações Farmacêuticas , Interações MedicamentosasRESUMO
We have previously shown that two enteral nutrition formulas suppressed gastric lesions induced by the oral administration of indomethacin (IND) in mice. However, the mechanism of their protective effect is unknown. In this study, the effect of the two enteral nutrition formulas on gastric lesions induced by subcutaneous IND injection was investigated, with the objective of exploring the possibility that they may interact directly with IND in the gastrointestinal tract. Ten-week-old, male, ICR mice were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition formula (25 mL/kg). IND was injected subcutaneously at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of mice given enteral nutrition formula was reduced to 56-89% and 34-61%, respectively, compared with the mice given purified water. The time courses of plasma IND concentrations were comparable among the three groups. These results suggested that the effect of these enteral nutrition formulas on gastric lesions did not originate from their direct interaction with IND in the gastrointestinal tract or their effect on the disposition of IND.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Nutrição Enteral/métodos , Indometacina/efeitos adversos , Úlcera Gástrica/prevenção & controle , Administração Oral , Animais , Alimentos Formulados , Mucosa Gástrica/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estômago/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologiaRESUMO
PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.
Assuntos
Complexos de Coordenação/farmacocinética , Síndrome dos Cabelos Torcidos/tratamento farmacológico , Tiossemicarbazonas/farmacocinética , Administração Oral , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C3H , Tamanho da PartículaRESUMO
In vitro-in vivo extrapolation (IVIVE) using human liver microsomes has been widely used to predict metabolic clearance, but some of the factors used in the process of prediction show variability for the same compound: notably, microsomal intrinsic clearance values corrected by the unbound fraction (CLint, u), physiological parameters used for scale-up, and the source of in vivo clearance data.The purpose of this study was to assess the correlation between in vitro and in vivo CLint with a focus on factors showing variability using four cytochrome P450 (CYP)3A substrates.We surveyed in vivo clearance values in literature and also determined the microsomal CLint, u values. A scaling factor (SFdirect) was defined as in vivo CLint divided by the microsomal CLint, u, which ranged from 1190 to 2310 (mg protein per kg body weight). The application of a mean SFdirect of 1600 (mg protein per kg body weight) and further normalization by the microsomal CLint, u values of midazolam, the most commonly used substrate, resulted in improved prediction accuracy for CLint, u values from various microsomal batches.The results suggest the normalization of variability might be useful for predicting the in vivo CLint.
Assuntos
Taxa de Depuração Metabólica , Microssomos Hepáticos/fisiologia , Citocromo P-450 CYP3A , Hepatócitos , Humanos , Cinética , Fígado , Midazolam/metabolismoRESUMO
Ceftriaxone (CTRX) is a third-generation cephalosporin commonly used to treat infections such as community-acquired pneumonia and urinary tract infections caused by mainly Gram-negative bacteria and some Gram-positive bacteria. Here, we report a case of a patient on hemodialysis who had chorea-like symptoms with high blood concentration of CTRX. A 74-year-old Japanese woman receiving hemodialysis was admitted with obstructive cholangitis and was started on CTRX therapy at a dose of 2 g every 24 hours. On the 6th day after starting administration of CTRX, chorea-like symptoms appeared. We suspected that her symptoms were caused by a high blood concentration of CTRX. We performed a series of blood sampling to determine the concentration of CTRX at different time points before and after discontinuing CTRX administration. CTRX concentrations were higher than those expected in healthy adults, and her chorea-like symptoms had disappeared from the second day of discontinuation of CTRX. The association between CTRX blood concentration and chorea-like symptoms is unclear. However, measuring a series of plasma or serum concentrations from symptom onset to disappearance suggested that chorea-like symptoms appeared when the concentration exceeded approximately 450 µg/mL. Care should be taken when administering CTRX to patients with cholestasis undergoing hemodialysis, as blood CTRX levels may rise unexpectedly and result in complications.
Assuntos
Antibacterianos , Ceftriaxona , Coreia/induzido quimicamente , Idoso , Antibacterianos/efeitos adversos , Antibacterianos/sangue , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Ceftriaxona/efeitos adversos , Ceftriaxona/sangue , Ceftriaxona/farmacocinética , Ceftriaxona/uso terapêutico , Colangite/tratamento farmacológico , Coreia/fisiopatologia , Feminino , Humanos , Diálise RenalRESUMO
We investigated the effects of enteral nutrition formula on non-steroidal anti-inflammatory drug (NSAID)-induced gastric lesions in mice. Male ICR mice aged 7-9 weeks old were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition (25 or 50 mL/kg each). Indomethacin (IND) was orally administered at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of the mice given enteral nutrition showed a significant, dose-dependent decrease compared to the purified water-treated group, and no significant difference was seen between the two enteral nutrition-treated groups. Comparable time courses of plasma IND concentrations suggest that enteral nutrition does not inhibit gastrointestinal absorption of IND. Our findings indicate that administering enteral nutrition could inhibit the onset of NSAID-induced gastric ulcers.
Assuntos
Nutrição Enteral , Alimentos Formulados , Indometacina/toxicidade , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Úlcera Gástrica/patologiaRESUMO
Creatinine is excreted into urine by glomerular filtration and renal tubular secretion through drug transporters such as organic anion transporter 2 (OAT2), organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. We aimed to investigate whether our method for estimating percentage changes in serum creatinine concentration (SCr) and creatinine clearance (CLcre) from the baseline is applicable for studying renal transporter inhibitors. We tested 14 compounds (cimetidine, cobicistat, dolutegravir, dronedarone, DX-619, famotidine, INCB039110, nizatidine, ondansetron, pyrimethamine, rabeprazole, ranolazine, trimethoprim, and vandetanib), which were reported to cause reversible changes in SCr and/or CLcre in healthy subjects excluding elderly. Percentage changes were estimated from the relative contributions of the forementioned transporters to CLcre and competitive inhibition by these compounds at their maximum plasma unbound concentrations. For 7 and 9 out of these compounds, changes in SCr and/or CLcre were estimated within 2- and 3-fold of observed values, respectively. Less than 10% changes in SCr and/or CLcre caused by cobicistat, dolutegravir, and rabeprazole were reproduced as such by our method. These findings suggest that our method can be used to estimate changes in SCr and CLcre caused by competitive inhibitions of renal drug transporters.
Assuntos
Creatinina/sangue , Creatinina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Inibidores da Bomba de Prótons/farmacologia , Transporte Biológico/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Proteínas de Transporte de Cátions Orgânicos/metabolismoRESUMO
AIMS: Vonoprazan, a new class of potassium-competitive proton pump inhibitors has been found to attenuate the antiplatelet function of clopidogrel in a recent clinical study, despite weak in vitro activity against CYP2C19. To elucidate the mechanism of this interaction, the present study investigated the effects of esomeprazole and vonoprazan on the pharmacokinetics of proguanil, a CYP2C19 substrate. METHODS: Seven healthy male volunteers (CYP2C19 extensive metabolizers) received a single oral administration of 100 mg proguanil/250 mg atovaquone (control phase), oral esomeprazole (20 mg) for 5 days followed by proguanil/atovaquone (esomeprazole phase) and oral vonoprazan (20 mg) for 5 days followed by proguanil/atovaquone (vonoprazan phase). Concentrations of proguanil and its metabolite, cycloguanil, in plasma and urine in each phase were determined using liquid chromatography-tandem mass spectrometry. RESULTS: Coadministration with proton pump inhibitors resulted in increase and decrease in the area under the plasma concentration-time curve (AUC) of proguanil and cycloguanil, respectively, significantly reducing their AUC ratio (cycloguanil/proguanil) to 0.317-fold (95% confidence interval [CI] 0.256-0.379) and 0.507-fold (95% CI 0.409-0.605) in esomeprazole phase and vonoprazan phase, respectively. Esomeprazole and vonoprazan also significantly reduced the apparent formation clearance (cumulative amount of cycloguanil in urine divided by AUC of proguanil) to 0.324-fold (95% CI 0.212-0.436) and 0.433-fold (95% CI 0.355-0.511), respectively, without significant changes in renal clearance of proguanil and cycloguanil. CONCLUSIONS: Although further studies are needed, both esomeprazole and vonoprazan potentially inhibit CYP2C19 at clinical doses, suggesting caution in the coadministration of these drugs with CYP2C19 substrates.
Assuntos
Esomeprazol/farmacologia , Proguanil/farmacocinética , Inibidores da Bomba de Prótons/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Adulto , Área Sob a Curva , Atovaquona/administração & dosagem , Cromatografia Líquida , Citocromo P-450 CYP2C19/metabolismo , Combinação de Medicamentos , Esomeprazol/administração & dosagem , Humanos , Masculino , Proguanil/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Sulfonamidas/administração & dosagem , Espectrometria de Massas em Tandem , Triazinas/farmacocinética , Adulto JovemRESUMO
The antidiabetic drugs glibenclamide, repaglinide, and nateglinide are well-known substrates for hepatic uptake transporters of the organic anion transporting polypeptide (OATP) family and metabolizing enzymes of the cytochrome P450 (CYP) 2C subfamily. The systemic exposure of these drugs varies substantially among individuals, impacted by genetic polymorphisms of transporters and metabolizing enzymes as well as drug-drug interactions. The use of the conventional in vitro-in vivo extrapolation (IVIVE) method was found to underestimate their hepatic intrinsic clearance (CLint,all); the clinically observed CLint,all values were ≥10-fold higher than the predicted values from in vitro data. In order to improve the accuracy in predicting CLint,all of these drugs, the following modifications were implemented; i) the extended clearance concept was applied during IVIVE processes, ii) albumin was added to metabolic assays using human liver microsomes (to minimize the impact of intrinsic inhibitors on kinetic parameters for CYP2C-mediated metabolism) and to hepatic uptake assays (to accommodate the enhanced hepatic uptake observed with albumin-bound drugs), and iii) differing rates of efflux and influx via diffusion were used. The IVIVE method with these modifications yielded the predicted CLint,all values from in vitro data in closer agreement with the CLint,all values observed in vivo; the fold differences between the predicted and observed CLint,all values reduced from 13-15 to 5.9-6.7. Our current approach offers an improvement in the prediction of CLint,all and further investigations are warranted to enhance the prediction accuracy of IVIVE.
Assuntos
Albuminas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Hipoglicemiantes/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/metabolismo , Modelos Biológicos , Carbamatos/farmacocinética , Glibureto/farmacocinética , Células HEK293 , Hepatócitos/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Taxa de Depuração Metabólica , Microssomos Hepáticos/metabolismo , Nateglinida/farmacocinética , Piperidinas/farmacocinética , 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/metabolismoRESUMO
Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CLcre), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters.
Assuntos
Creatinina/sangue , Inibidores do Citocromo P-450 CYP2C8/sangue , Rim/metabolismo , Modelos Biológicos , Trimetoprima/sangue , Inibidores do Citocromo P-450 CYP2C8/farmacologia , Voluntários Saudáveis , Humanos , Rim/efeitos dos fármacos , Trimetoprima/farmacologiaRESUMO
We have previously reported that the microsomal activities of CYP2C8 and CYP3A4 largely depend on the buffer condition used in in vitro metabolic studies, with different patterns observed between the 2 isozymes. In the present study, therefore, the possibility of buffer condition dependence of the fraction metabolized by CYP2C8 (fm2C8) for repaglinide, a dual substrate of CYP2C8 and CYP3A4, was estimated using human liver microsomes under various buffer conditions. Montelukast and ketoconazole showed a potent and concentration-dependent inhibition of CYP2C8-mediated paclitaxel 6α-hydroxylation and CYP3A4-mediated triazolam α-hydroxylation, respectively, without dependence on the buffer condition. Repaglinide depletion was inhibited by both inhibitors, but the degree of inhibition depended on buffer conditions. Based on these results, the contribution of CYP2C8 in repaglinide metabolism was estimated to be larger than that of CYP3A4 under each buffer condition, and the fm2C8 value of 0.760, estimated in 50 mM phosphate buffer, was the closest to the value (0.801) estimated in our previous modeling analysis based on its concentration increase in a clinical drug interaction study. Researchers should be aware of the possibility of buffer condition affecting the estimated contribution of enzyme(s) in drug metabolism processes involving multiple enzymes.
Assuntos
Carbamatos/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Hipoglicemiantes/metabolismo , Microssomos Hepáticos/metabolismo , Piperidinas/metabolismo , Acetatos/farmacologia , Soluções Tampão , Ciclopropanos , Indutores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações Medicamentosas , Humanos , Cetoconazol/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Quinolinas/farmacologia , SulfetosRESUMO
1. Buffer conditions in in vitro metabolism studies using human liver microsomes (HLM) have been reported to affect the metabolic activities of several cytochrome P450 (CYP) isozymes in different ways, although there are no reports about the dependence of CYP2C8 activity on buffer conditions. 2. The present study investigated the effect of buffer components (phosphate or Tris-HCl) and their concentration (10-200 mM) on the CYP2C8 and CYP3A4 activities of HLM, using paclitaxel and triazolam, respectively, as marker substrates. 3. The Km (or S50) and Vmax values for both paclitaxel 6α-hydroxylation and triazolam α- and 4-hydroxylation, estimated by fitting analyses based on the Michaelis-Menten or Hill equation, greatly depended on the buffer components and their concentration. 4. The CLint values in phosphate buffer were 1.2-3.0-fold (paclitaxel) or 3.1-6.4-fold (triazolam) higher than in Tris-HCl buffer at 50-100 mM. These values also depended on the buffer concentration, with a maximum 2.3-fold difference observed between 50 and 100 mM which are both commonly used in drug metabolism studies. 5. These findings suggest the necessity for optimization of the buffer conditions in the quantitative evaluation of metabolic clearances, such as in vitro-in vivo extrapolation and also estimating the contribution of a particular enzyme in drug metabolism.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Microssomos Hepáticos/enzimologia , Paclitaxel/farmacocinética , Triazolam/farmacocinética , Humanos , Hidroxilação , Isoenzimas/metabolismoRESUMO
In a transcellular transport study, the apparent permeability coefficient (Papp) of a compound is evaluated using the range by which the amount of compound accumulated on the receiver side is assumed to be proportional to time. However, the time profile of the concentration of the compound in receiver (C3) often shows a lag time before reaching the linear range and later changes from linear to steady state. In this study, the linear range needed to calculate Papp in the C3-time profile was evaluated by a 3-compartment model. C3 was described by an equation with two steady states (C3=A3(1-e(-αt))+B3(1-e(-ßt)), α>ß), and by a simple approximate line (C3=A3-A3×αt) in the time range of 3/αAssuntos
Modelos Biológicos
, Transcitose
, Células CACO-2
, Humanos
, Absorção Intestinal
, Cinética
, Permeabilidade
, Fatores de Tempo
RESUMO
The purpose of this study was to predict the drug-drug interactions (DDIs) via CYP3A4 by estimating the extent of hepatic CYP3A4 inhibition based on a physiologically based pharmacokinetic (PBPK) model of both substrate and inhibitor and the increase in the intestinal availability (Fg ) due to the enzyme inhibition. For the DDIs resulting from reversible inhibition of CYP3A4, the prediction using in vivo Ki values estimated from other clinical DDI studies and predicted in vivo Ki values calculated using the correlation between the log P and the in vivo Ki /in vitro Ki ratio was more accurate than that using in vitro Ki values. Incorporating inhibition of both intestinal and hepatic metabolism resulted in better prediction than that obtained considering inhibition in the liver alone, and all the DDIs (AUC increase by the inhibitor) were predicted within 2-fold accuracy when in vivo Ki values were used. In addition, Fg values were successfully back-calculated from the clinical DDI data based on the present model. In conclusion, the present PBPK model incorporating the in vivo Ki values was found to be useful for quantitative prediction of clinical DDIs and for estimation of the Fg values for CYP3A4 substrates for which intravenous data were not available.