Organic Anion Transporting Polypeptide 1B1 Research Articles

Development of a Physiologically Based Pharmacokinetic Model to Evaluate Dosing Regimens of Cyclosporine as a Precipitant of Organic Anion Transporting Polypeptide 1B (OATP1B)- and CYP3A4-Mediated Drug-Drug Interactions.

Cyclosporine (cyclosporin A or CsA), a clinically relevant but nonspecific inhibitor of hepatic organic anion transporting polypeptides (OATPs), is used for assessing transporter-mediated drug-drug interactions (DDIs) at varying dosing regimens. We developed a physiologically based pharmacokinetic model to reproduce CsA pharmacokinetics (PK) and effect of CsA on substrates of OATPs and cytochrome P450 (CYP)3A4. The model was built using intravenous and oral CsA clinical PK and DDI data in healthy volunteers. The model reproduces single- and multiple-dose clinical CsA PK from numerous studies with simulated/observed AUC and Cmax within 0.59-1.75 following oral CsA dosing. As an object of CYP3A4, the model reproduces the observed effect of ketoconazole and grapefruit juice on CsA PK. CsA inhibition constants against CYP3A4 and hepatic OATPs were estimated to reproduce clinical DDIs with CYP3A index substrate midazolam (MDZ) and OATP1B biomarker coproporphyrin-I, and confirmed with felodipine and pitavastatin, verifying the model for inhibition of hepatic CYP3A4 and OATPs in healthy volunteers. A review of clinical data herein indicates that most clinical DDI studies utilize a single dose of CsA and for certain clinical substrates, a counterintuitive decrease in half-life following CsA administration has been observed (similar to single-dose rifampin DDIs). Using the currently developed CsA model, we predicted the effect of various single- and multiple-dose CsA regimens against OATP1B substrate and MDZ models. Depending on the OATP1B substrate characteristics, 200 mg CsA twice daily or a single 600 mg dose reasonably mimic simulated continuous OATP1B inhibition and single-dose rifampin, albeit with predicted weak-to-moderate CYP3A4 inhibition.

Guiding precision medicine strategy for intravenous ginsenosides via pharmacokinetic-informed bioinformatic approaches: a study on XueShuanTong.

Guiding precision medicine strategy for intravenous ginsenosides via pharmacokinetic-informed bioinformatic approaches: a study on XueShuanTong.

The Effect of Radixin on the Function and Expression of Organic Anion Transporting Polypeptide 1B1

Organic anion transporting polypeptide 1B1 (OATP1B1) is selectively expressed at the basolateral membrane of human hepatocytes and plays a crucial role in the absorption of various xenobiotic compounds, including many important clinical drugs. Oligomerization with regulatory proteins is a common mechanism for regulating membrane protein functions. In the present study, we found that knocking down the scaffold protein radixin, which is the major member of the ERM family expressed in the liver, significantly enhanced the uptake function of OATP1B1. On the other hand, the overexpression of the phospho-mimic form of radixin (radixin-D) reduced the uptake function and cell surface level of OATP1B1, while the wild-type and phospho-dormant form of radixin (radixin-A) did not exhibit the same effect. Further investigation revealed that radixin interacts with OATP1B1. Activation of protein kinase C (PKC), which our previous study showed accelerates the internalization of OATP1B1, was found to increase the phosphorylation level of radixin associated with OATP1B1. The knockdown of radixin significantly diminished the suppressive effect of PKC on the function and cell surface levels of OATP1B1. These results suggested that OATP1B1 forms complexes with radixin, which may be phosphorylated by PKC, leading to reduced cell surface expression and activity of the transporter.

Role of Extracellular Histidine Residues for the Function and pH Sensitivity of Human Organic Anion Transporting Polypeptide 1B3.

Organic anion transporting polypeptide 1B3 (OATP1B3) is a liver-specific transporter that mediates uptake of various substances from blood into hepatocytes. The transport function of OATP1B3 was shown to be pH-sensitive. As the protonation state of extracellular histidine residues can be affected by the environmental pH, in the present study, the role of 7 extracellular histidine residues in the function and pH sensitivity of OATP1B3 has been examined. Our results showed that H115 had the most significant effect on the function of OATP1B3. The Cryo-EM structure of OATP1B3 indicated that H115 is involved in the binding and release of bicarbonate during a transport cycle. Functional studies on H115 mutants suggested that a hydrogen-bond forming group was preferred over a positively charged group at site 115, indicating that a hydrogen bond is optimum for bicarbonate's binding/release cycle. This may also explain why OATP1B3 showed lower transport function at pH 4.5 than at pH 7.4, as H115 is positively charged at pH 4.5 but neutral at pH 7.4. In addition, the H115A mutation largely compromised the pH sensitivity of OATP1B3, probably due to the loss of its protonation state switching capability. Taken together, H115 plays an important role in the function and pH sensitivity of OATP1B3.

Huachansu injection enhances anti-colorectal cancer efficacy of irinotecan and alleviates its induced intestinal toxicity through upregulating UGT1A1-OATP1B3 expression in vitro and in vivo.

Huachansu injection enhances anti-colorectal cancer efficacy of irinotecan and alleviates its induced intestinal toxicity through upregulating UGT1A1-OATP1B3 expression in vitro and in vivo.

Cancer-type OATP1B3-V1 is a functional plasma membrane transporter mediating increased uptake of chemotherapeutics in vitro and in vivo.

Cancer-type OATP1B3-V1 is a functional plasma membrane transporter mediating increased uptake of chemotherapeutics in vitro and in vivo.

Drug-drug interaction of paclitaxel and TAS-119, a novel aurora a kinase inhibitor, mediated by organic anion transporting polypeptide 1B1

Drug-drug interaction of paclitaxel and TAS-119, a novel aurora a kinase inhibitor, mediated by organic anion transporting polypeptide 1B1

In vitro and in silico evaluation of the interaction of yohimbine with drug transporters and cytochrome P450 isoenzymes.

In vitro and in silico evaluation of the interaction of yohimbine with drug transporters and cytochrome P450 isoenzymes.

Gadoxetic acid-enhanced magnetic resonance imaging predicts early nab-paclitaxel-induced peripheral neuropathy during pancreatic cancer treatment: A pilot study.

Gadoxetic acid-enhanced magnetic resonance imaging predicts early nab-paclitaxel-induced peripheral neuropathy during pancreatic cancer treatment: A pilot study.

Coproporphyrin I as an in vitro fluorescent probe to measure OATP1B1 transport activity.

Coproporphyrin I as an in vitro fluorescent probe to measure OATP1B1 transport activity.

Erlotinib-A substrate and inhibitor of OATP2B1: pharmacokinetics and CYP3A-mediated metabolism in rSlco2b1-/- and SLCO2B1+/+ rats.

Erlotinib-A substrate and inhibitor of OATP2B1: pharmacokinetics and CYP3A-mediated metabolism in rSlco2b1-/- and SLCO2B1+/+ rats.

Effect of tripterine on the pharmacokinetics of cyclosporine A and its mechanism in rats.

Tripterine is a key active component in Tripterygium wilfordii polyglycosides tablets. Cyclosporine A (CsA) is an immunosuppressive drug that is widely used in organ transplantation. The combined use of Tripterygium wilfordii and CsA can reportedly enhance the immunosuppressive effects of Cyclosporine whilst reducing its toxicity. Therefore, in the present study, a detection method for CsA concentration in rat blood samples was developed using liquid chromatography-mass spectrometry (MS)/MS. Reverse transcription-quantitative (RT-q) PCR and western blotting (WB) were used to examine the impact of tripterine on the expression of a variety of drug-metabolizing enzymes, drug transporters and nuclear receptors. Compared with that in the control group, the maximum concentration (Cmax) of CsA was found to be reduced across all tripterine dosage groups, where the area under the curve was significantly decreased in the 18 and 54 mg/kg groups. PCR and WB results indicated that tripterine inhibited the expression of cytochrome P450 (CYP) 3A1, CYP3A2, uridine diphosphate glucuronosyltransferase 1A1, organic anion-transporting polypeptide 1B2, p-glycoprotein 1, multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein, bile salt export pump (BSEP) and Na+-taurocholate co-transporting polypeptide (NTCP). These results suggest that tripterine's inhibition of NTCP, BSEP and MRP2 in the liver may disrupt bile acid circulation. Additionally, tripterine's activation of farnesoid X receptor in the intestine may limit bile acid synthesis, resulting in reduced CsA uptake into the bloodstream and inhibiting its enterohepatic circulation, ultimately leading to a decrease in CsA blood concentration. In addition, the combination of Tripterygium wilfordii and CsA have the prospect of joint clinical application. The present study demonstrated the inhibitory effect of tripterine on the pharmacokinetics of CsA, which could be of significance for the combined use of these two drugs.

Significance of gut breast cancer resistance protein versus organic anion transporting polypeptide 2B1 inhibition on rosuvastatin clinical drug-drug interactions.

Significance of gut breast cancer resistance protein versus organic anion transporting polypeptide 2B1 inhibition on rosuvastatin clinical drug-drug interactions.

Identification and Clinical Evaluation of Potential Biomarkers for Breast Cancer Resistance Protein (BCRP/ABCG2)

Clinical inhibition and genetic variation of the Breast Cancer Resistance Protein (BCRP/ABCG2) efflux transporter can significantly influence drug exposure, highlighting the need for reliable BCRP functional biomarkers. This study aimed to identify and evaluate biomarkers predictive of BCRP function in humans. A comprehensive analysis of metabolomic genome‐wide association studies (mGWAS) was conducted to discover potential BCRP biomarkers, followed by evaluation in in vitro transporter assays and a clinical drug–drug interaction (DDI) study. Across multiple mGWAS datasets, plasma concentrations of three herbicide derivatives—4‐hydroxychlorothalonil (4HC), 3‐bromo‐5‐chloro‐2,6‐dihydroxybenzoic acid (BCDBA), and 3,5‐dichloro‐2,6‐dihydroxybenzoic acid (DCDBA)—were significantly elevated (P < 5E‐8) in individuals carrying reduced function ABCG2 polymorphisms. These compounds were confirmed as novel BCRP substrates via transporter uptake assays and selected for clinical evaluation alongside riboflavin, a known BCRP substrate and potential BCRP biomarker. In a DDI study with 11 healthy subjects, eltrombopag, a BCRP inhibitor, increased rosuvastatin concentrations by approximately twofold (P = 0.002). No significant changes in the plasma concentrations of organic anion transporting polypeptide 1B (OATP1B) biomarkers (CP‐I and CP‐III) or potential BCRP biomarkers (4HC, BCDBA, DCDBA, or riboflavin) were observed. Notably, two subjects were heterozygous carriers for the ABCG2 p.Q141K variant and exhibited significantly higher baseline concentrations of 4HC (P = 0.004) and BCDBA (P = 0.0003), consistent with reduced BCRP function. These findings suggest that 4HC and BCDBA are promising biomarkers for baseline BCRP function in specific populations, such as those harboring reduced function genetic polymorphisms, but do not appear suitable for detecting acute BCRP inhibition.

Association of SLCO1B1 genetic variants with neonatal hyperbilirubinemia: a consolidated analysis of 36 studies

BackgroundThis study aimed to assess the link between polymorphisms in the SLCO1B1 gene, responsible for the organic anion transporter polypeptide 1B1 (OATP1B1), and the risk of neonatal hyperbilirubinemia.MethodsA comprehensive literature review was performed utilizing PubMed, Web of Knowledge, and CNKI, culminating on December 1, 2023, focusing on studies published before this date. The search employed relevant keywords and MeSH terms related to hyperbilirubinemia and genetic factors. The inclusion criteria focused on original case-control, longitudinal, or cohort studies, with no restrictions on language or publication year. Correlations were quantified as odds ratios (ORs) with 95% confidence intervals (CIs) using Comprehensive Meta-Analysis software.ResultsThirty-six case-control studies drawn from 22 publications encompassed a total of 5,186 cases and 5,561 controls. Among these, 20 studies involved the rs2306283 polymorphism, with 2,602 cases and 2,832 controls, while 16 studies focused on rs4149056, including 2,584 cases and 2,729 controls. Sample sizes varied significantly, ranging from 41 to 447 cases and 47 to 544 controls. Pooled analysis indicated no significant associations for rs2306283 overall or within Asian and Caucasian subgroups; however, significant associations emerged within the Chinese subgroup under both the allele model (OR = 1.297, 95% CI 1.012–1.662, p = 0.040) and the dominant model (OR = 1.344, 95% CI 1.013–1.784, p = 0.041), suggesting a potential risk tied to the G allele. Conversely, the examination of rs4149056 revealed no significant associations across all comparisons, including ethnic subgroup analyses.ConclusionsThe results imply that polymorphisms rs2306283 and rs4149056 in the SLCO1B1 gene are generally not associated with the risk of neonatal hyperbilirubinemia in overall population. Nevertheless, rs2306283 may pose an increased risk within the Chinese population, while rs4149056 shows no significant correlations across various groups. Further research is needed to clarify these implications and investigate other genetic factors related to neonatal hyperbilirubinemia.

In Vitro and Clinical Evaluations of UGT1A1-, P-gp-, OATP1B1-, and BCRP-Mediated Drug-Drug Interactions of Belumosudil, a Potent ROCK2 Inhibitor.

Belumosudil is an oral selective rho-associated coiled-coil containing protein kinase 2 inhibitor, approved as a treatment for chronic graft-versus-host disease. Prior clinical studies demonstrated that coadministration with strong CYP3A4 inducers or proton pump inhibitors requires dose modification of belumosudil. In vitro assessments suggested that belumosudil may inhibit uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), P-glycoprotein (P-gp), organic anion transporting polypeptide 1B1 (OATP1B1), and breast cancer resistance protein (BCRP), resulting in drug-drug interactions (DDIs). This three-part clinical DDI study (NCT05806567) was conducted to assess the effect of multiple doses of belumosudil (200 mg daily) on the single-dose pharmacokinetics of raltegravir (UGT1A1-sensitive substrate), dabigatran etexilate (P-gp-sensitive substrate), and rosuvastatin calcium (OATP1B1/BCRP-sensitive substrate). Although there was no marked change in raltegravir exposure after coadministration with belumosudil, exposure to the glucuronide metabolite was decreased by 39.6% (area under the curve from time 0 to the time of last measurable concentration [AUC0-last]) and 42.4% (maximum observed concentration [Cmax]), suggesting that belumosudil is an in vivo inhibitor of UGT1A1. There was an approximate 2-fold increase in Cmax, AUC0-last, and AUC from time 0 extrapolated to infinity (AUC0-inf) for dabigatran etexilate, suggesting a potential and clinically relevant DDI for belumosudil and sensitive P-gp substrates. Cmax and AUC0-last for rosuvastatin calcium increased by 3.6-fold and 4.6-fold, respectively, suggesting a clinically relevant interaction with drugs that are substrates of OATP1B1 or BCRP. There was no impact of coadministration with raltegravir, dabigatran etexilate, or rosuvastatin calcium on belumosudil pharmacokinetics, and belumosudil was well tolerated.

S-Nitrosoglutathione Is Not a Substrate of OATP1B1, but Stimulates Its Expression and Activity.

S-nitrosoglutathione (GSNO) is the S-nitrosated derivative of glutathione (GSH). GSNO is an endogenous class of NO donors and a natural NO depot in biological systems. Organic anion transporting polypeptide 1B1 (OATP1B1) is an influx transporter that is expressed in the liver. OATP1B1 plays an important role in the transport of endogenous and exogenous substances. Various pathways for the regulation of OATP1B1 have been described. In the present study, the involvement of OATP1B1 in GSNO transport and the regulation of OATP1B1 by GSNO was examined. For HEK293-OATP1B1, it has been shown that GSNO is not a substrate of OATP1B1, but OATP1B1 can participate in the transport of GSH across the cell membrane. GSNO at concentrations of 1-100 μM and exposure for 3 h do not affect the expression and activity of OATP1B1, but exposure for 24 and 72 h stimulates the expression of the SLCO1B1 gene, OATP1B1, and transporter activity. Up-regulation of OATP1B1 by GSNO is carried out through the NO-cGMP signaling pathway, Nrf2, and LXRa.

Genotype, Ethnicity, and Drug-Drug Interaction Modeling as Means of Verifying Transporter Biomarker PBPK Model: The Coproporphyrin-I Story.

Coproporphyrin-I (CP-I) is a selective endogenous biomarker of organic anion-transporting polypeptide (OATP)1B. Multiple CP-I PBPK models with differing input parameters have been reported so far. This study proposed a harmonized CP-I PBPK model and evaluated its ability to predict the effect of ethnicity, SLCO1B1 genotype c.521T>C, and sex on CP-I baseline and CP-I-drug interactions using the largest clinical dataset to date. The CP-I PBPK model successfully predicted CP-I plasma baseline from 731 subjects, with 97% of predictions within 1.5-fold of the observed data. Prediction of weak, moderate, and strong OATP1B-mediated interactions with probenecid, low-dose cyclosporine, and rifampicin, respectively, was evaluated with 21 datasets. Overall, > 76% of CP-I CmaxR and AUCR were predicted within the Guest criterion. Invivo OATP1B Ki estimated by the biomarker model was up to ninefold lower compared to invitro values. Sensitivity analyses showed differences in estimated invivo Ki depending on the assumed contribution of non-inhibited/parallel pathway (renal) for CP-I (0%-15%), highlighting the need to consider this factor when using biomarker PBPK models for such purposes. Finally, the appropriate metric for monitoring CP-I was evaluated for inhibitors with different potency and PK relative to CP-I. In the case of strong/moderate OATP1B inhibitors with short t1/2, CmaxR was the most sensitive metric for monitoring CP-I OATP1B interactions, whereas both CmaxR and AUCR were applicable for inhibitors with long t1/2. The current study provides a harmonized CP-I PBPK model, together with recommendations to support the optimal design of prospective clinical trials for the assessment of OATP1B-mediated DDIs using this biomarker.

Efficient protein quantification in drug metabolism and pharmacokinetics with an accelerated proteomic workflow.

Efficient protein quantification in drug metabolism and pharmacokinetics with an accelerated proteomic workflow.

Elucidating Contributions of Drug Transporters/Enzyme to Nonlinear Pharmacokinetics of Grazoprevir by PBPK Modeling With a Cluster Gauss-Newton Method.

Grazoprevir (GZR), a direct-acting agent for hepatitis C virus, is recognized as a substrate for organic anion transporting polypeptide 1B (OATP1B), cytochrome P450 3A (CYP3A), and P-glycoprotein (P-gp). The objective of the present study was to elucidate the contribution of these molecules to the nonlinear pharmacokinetics of GZR using a physiologically based pharmacokinetic (PBPK) model. Utilizing plasma concentration-time profiles of GZR derived from reported dose-escalation (50-800 mg) clinical studies and cumulative excretion data, around 10 parameters, including Michaelis constants (Km) for OATP1B, CYP3A, and P-gp, were estimated via a cluster Gauss-Newton method (CGNM). Parameter combinations that could reproduce the clinical data of GZR were obtained; however, discrepancies were noted between the invivo estimated Km and the corresponding invitro Km. Next, by incorporating the invitro Km values into our PBPK-CGNM analyses utilizing a penalized parameter method, newly obtained parameter combinations appropriately reflected both the invivo and invitro observations. Particularly regarding OATP1B, while saturation of uptake was not clearly observed in the invitro experiments without human serum albumin (HSA), Km values capable of explaining invivo saturation were obtained under physiological HSA concentrations. By estimating the extent of saturation for each molecule in the liver and intestine and conducting sensitivity analyses of the Km values, it was inferred that OATP1B3 contributed the most to the nonlinearity of plasma GZR concentrations, followed by P-gp. In conclusion, the PBPK-CGNM, supplemented by penalized invitro parameters, was shown to be effective for analyzing complex pharmacokinetics involving drug transporters and enzymes.