Dataset Information

Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction.

ABSTRACT: As rifampicin can cause the induction and inhibition of multiple metabolizing enzymes and transporters, it has been challenging to accurately predict the complex drug-drug interactions (DDIs). We previously constructed a physiologically-based pharmacokinetic (PBPK) model of rifampicin accounting for the components for the induction of cytochrome P450 (CYP) 3A/CYP2C9 and the inhibition of organic anion transporting polypeptide 1B (OATP1B). This study aimed to expand and verify the PBPK model for rifampicin by incorporating additional components for the induction of OATP1B and CYP2C8 and the inhibition of multidrug resistance protein 2. The established PBPK model was capable of accurately predicting complex rifampicin-induced alterations in the profiles of glibenclamide, repaglinide, and coproporphyrin I (an endogenous biomarker of OATP1B activities) with various dosing regimens. Our comprehensive rifampicin PBPK model may enable quantitative prediction of DDIs across diverse potential victim drugs and endogenous biomarkers handled by multiple metabolizing enzymes and transporters.

SUBMITTER: Asaumi R

PROVIDER: S-EPMC6875706 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction.

Asaumi Ryuta R Menzel Karsten K Lee Wooin W Nunoya Ken-Ichi KI Imawaka Haruo H Kusuhara Hiroyuki H Sugiyama Yuichi Y

CPT: pharmacometrics & systems pharmacology 20190905 11

As rifampicin can cause the induction and inhibition of multiple metabolizing enzymes and transporters, it has been challenging to accurately predict the complex drug-drug interactions (DDIs). We previously constructed a physiologically-based pharmacokinetic (PBPK) model of rifampicin accounting for the components for the induction of cytochrome P450 (CYP) 3A/CYP2C9 and the inhibition of organic anion transporting polypeptide 1B (OATP1B). This study aimed to expand and verify the PBPK model for ...[more]

PMID: 31420941

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Project description:Organic anion transporting polypeptide 2B1 (OATP2B1, gene SLCO2B1) is an uptake transporter that is thought to determine drug disposition and in particular, the oral absorption of medications. At present, the clinical relevance of SLCO2B1 genetic variation on pharmacokinetics is poorly understood. We sought to determine the functional activity of 5 of the most common missense OATP2B1 variants (c.76_84del, c.601G>A, c.917G>A, c.935G>A, and c.1457C>T) and a predicted dysfunctional variant (c.332G>A) in vitro. Furthermore, we measured the basal plasma concentrations of endogenous OATP2B1 substrates, namely estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate, coproporphyrin I (CPI), and CPIII, and assessed their relationships with SLCO2B1 genotypes in 93 healthy participants. Compared to reference OATP2B1, the transport activities of the c.332G>A, c.601G>A and c.1457C>T variants were reduced among the substrates examined (estrone sulfate, DHEAS, CPI, CPIII and rosuvastatin), although there were substrate-dependent effects. Lower transport function of OATP2B1 variants could be explained by diminished cell surface expression. Other OATP2B1 variants (c.76-84del, c.917G>A and c.935G>A) had similar activity to the reference transporter. In the clinical cohort, the SLCO2B1 c.935G>A allele was associated with both higher plasma CPI (42%) and CPIII (31%) concentrations, while SLCO2B1 c.917G>A was linked to lower plasma CPIII by 28% after accounting for the effects of age, sex, and SLCO1B1 genotypes. No association was observed between SLCO2B1 variant alleles and estrone sulfate or DHEAS plasma concentrations, however 45% higher plasma pregnenolone sulfate level was associated with SLCO2B1 c.1457C>T. Taken together, we found that the impacts of OATP2B1 variants on transport activities in vitro were not fully aligned with their associations to plasma concentrations of endogenous substrates in vivo. Additional studies are required to determine whether circulating endogenous substrates reflect OATP2B1 activity.

Project description:OBJECTIVE:Recent innovations in biology are boosting gene and cell therapy, but monitoring the response to these treatments is difficult. The purpose of this study was to find an MRI-reporter gene that can be used to monitor gene or cell therapy and that can be delivered without a viral vector, as viral vector delivery methods can result in long-term complications. MATERIALS AND METHODS:CMV promoter-human organic anion transporting polypeptide 1B3 (CMV-hOATP1B3) cDNA or CMV-blank DNA (control) was transfected into HEK293 cells using Lipofectamine. OATP1B3 expression was confirmed by western blotting and confocal microscopy. In vitro cell phantoms were made using transfected HEK293 cells cultured in various concentrations of gadoxetic acid for 24 hours, and images of the phantoms were made with a 9.4T micro-MRI. In vivo xenograft tumors were made by implanting HEK293 cells transfected with CMV-hOATP1B3 (n = 4) or CMV-blank (n = 4) in 8-week-old male nude mice, and MRI was performed before and after intravenous injection of gadoxetic acid (1.2 ?L/g). RESULTS:Western blot and confocal microscopy after immunofluorescence staining revealed that only CMV-hOATP1B3-transfected HEK293 cells produced abundant OATP1B3, which localized at the cell membrane. OATP1B3 expression levels remained high through the 25th subculture cycle, but decreased substantially by the 50th subculture cycle. MRI of cell phantoms showed that only the CMV-hOATP1B3-transfected cells produced a significant contrast enhancement effect. In vivo MRI of xenograft tumors revealed that only CMV-hOATP1B3-transfected HEK293 tumors demonstrated a T1 contrast effect, which lasted for at least 5 hours. CONCLUSION:The human endogenous OATP1B3 gene can be non-virally delivered into cells to induce transient OATP1B3 expression, leading to gadoxetic acid-mediated enhancement on MRI. These results indicate that hOATP1B3 can serve as an MRI-reporter gene while minimizing the risk of long-term complications.

Project description:ObjectiveTo detect the expression level of organic anion-transporting polypeptide 1B3 (OATP1B3) in hepatocellular carcinoma (HCC) and to determine the relationship between OATP1B3 expression, clinicopathological features, and prognosis.MethodsImmunohistochemical (IHC) staining was performed to detect the expression of OATP1B3 in 131 HCC specimens and in 89 adjacent nontumorous tissues. Moreover, the expression levels of OATP1B3 in 30 pairs of tumor and matched adjacent nontumorous tissues were detected by quantitative real-time polymerase chain reaction, and 34 pairs of tumor and matched adjacent nontumorous tissues were detected by Western blotting. The χ2 test was applied to analyze the correlation between OATP1B3 expression and the clinical parameters of HCC patients. The prognostic value of OATP1B3 in HCC patients was estimated by Kaplan-Meier survival analysis and the Cox stepwise proportional hazards model.ResultsCompared with that in adjacent nontumorous tissues (25.8%, 23/89), OATP1B3 expression was significantly downregulated in tumor tissues (59.5%, 78/131) (P < 0.0001). Moreover, OATP1B3 expression was markedly correlated with tumor size, recurrence, tumor differentiation, and tumor node metastasis (TNM) stage (P < 0.05 for each). However, age, sex, tumor capsule status, HBsAg, cirrhosis, tumor number, vascular invasion, and serum alpha fetoprotein were not associated with OATP1B3 expression. The overall survival (OS) and disease-free survival (DFS) of HCC patients who had high expression of OATP1B3 were significantly longer than those of patients with low expression (33.0% vs 12.9%, P = 0.001; 18.8% vs 5.3%, P < 0.0001). Cox multivariate analysis showed that OATP1B3, invasion, and TNM stage (P < 0.05 for each) were independent prognostic factors of OS in HCC patients and that OATP1B3 and TNM stage (both P < 0.05) were independent prognostic factors of DFS in HCC patients.ConclusionsThe expression of OATP1B3 in HCC patients was significantly lower than that in adjacent nontumorous tissues. OATP1B3 expression may be a potential prognostic marker in HCC patients.

Dataset Information

Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction.

Publications

Expanded Physiologically-Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction.

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