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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 4/2018

Open Access 01-04-2018 | Original Research Article

Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis

Authors: Rui Li, Hugh A. Barton

Published in: Clinical Pharmacokinetics | Issue 4/2018

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Abstract

Background

Ethnic variability in the pharmacokinetics of organic anion transporting polypeptide (OATP) 1B1 substrates has been observed, but its basis is unclear. A previous study hypothesizes that, without applying an intrinsic ethnic variability in transporter activity, allele frequencies of transporters cannot explain observed ethnic variability in pharmacokinetics. However, this hypothesis contradicts the data collected from compounds that are OATP1B1 substrates but not breast cancer resistance protein (BCRP) substrates.

Objective

The objective of this study is to evaluate a hypothesis that is physiologically reasonable and more consistent with clinical observations.

Methods

We evaluated if allele frequencies of two transporters (OATP1B1 and BCRP) are key contributors to ethnic variability. In this hypothesis, the same genotype leads to the same activity independent of ethnicity, in contrast to the previous hypothesis of intrinsic ethnic variability in OATP1B1 activity. As a validation, we perform mechanistic pharmacokinetic modeling for SLCO1B1 (encoding OATP1B1) and ABCG2 (encoding BCRP) genotyped pharmacokinetic data from 18 clinical studies with healthy Caucasian and/or Asian subjects.

Results

Simulations based on the current hypothesis reasonably describe SLCO1B1 and ABCG2 genotyped pharmacokinetic time course data for five transporter substrates (atorvastatin, pitavastatin, pravastatin, repaglinide, and rosuvastatin) in Caucasian and Asian populations.

Conclusion

This hypothesis covers the observations that can (e.g., ethnic differences in rosuvastatin pharmacokinetics) or cannot (e.g., lack of differences for pitavastatin pharmacokinetics) be explained by the previous hypothesis. It helps to characterize sources of ethnic variability and provides a foundation for predicting ethnic variability in transporter substrate pharmacokinetics.
Appendix
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Literature
1.
Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63(1):157–81.CrossRefPubMed
2.
Tomita Y, Maeda K, Sugiyama Y. Ethnic variability in the plasma exposures of OATP1B1 substrates such as HMG-CoA reductase inhibitors: a kinetic consideration of its mechanism. Clin Pharmacol Ther. 2013;94(1):37–51.CrossRefPubMed
3.
Peng KW, et al. Ethnic variability in the expression of hepatic drug transporters: absolute quantification by an optimized targeted quantitative proteomic approach. Drug Metab Dispos. 2015;43(7):1045–55.CrossRefPubMed
4.
Thomsen MS, et al. Pharmacokinetics of repaglinide in healthy caucasian and Japanese subjects. J Clin Pharmacol. 2003;43(1):23–8.CrossRefPubMed
5.
Warrington S, Nagakawa S, Hounslow N. Comparison of the pharmacokinetics of pitavastatin by formulation and ethnic group: an open-label, single-dose, two-way crossover pharmacokinetic study in healthy Caucasian and Japanese men. Clin Drug Investig. 2011;31(10):735–43.CrossRefPubMed
6.
Li R, et al. A “middle-out” approach to human pharmacokinetic predictions for OATP substrates using physiologically-based pharmacokinetic modeling. J Pharmacokinet Pharmacodyn. 2014;41(3):197–209.CrossRefPubMed
7.
Keskitalo JE, et al. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2009;86(2):197–203.CrossRefPubMed
8.
Wan Z, et al. Marked alteration of rosuvastatin pharmacokinetics in healthy Chinese with ABCG2 34G>A and 421C>A homozygote or compound heterozygote. J Pharmacol Exp Ther. 2015;354(3):310–5.CrossRefPubMed
9.
Shah DK, Betts AM. Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human. J Pharmacokinet Pharmacodyn. 2012;39(1):67–86.CrossRefPubMed
10.
Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57.CrossRefPubMed
11.
Martin PD, et al. Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther. 2003;25(10):2553–63.CrossRefPubMed
12.
Singhvi SM, et al. Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br J Clin Pharmacol. 1990;29(2):239–43.CrossRefPubMedPubMedCentral
13.
Birmingham BK, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States. Eur J Clin Pharmacol. 2015;71(3):329–40.CrossRefPubMed
14.
15.
Haario H, et al. DRAM: efficient adaptive MCMC. Stat Comput. 2006;16(4):339–54.CrossRef
16.
Pasanen MK, et al. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2007;82(6):726–33.CrossRefPubMed
17.
Oh ES, et al. Impact of ABCC2, ABCG2 and SLCO1B1 polymorphisms on the pharmacokinetics of pitavastatin in humans. Drug Metab Pharmacokinet. 2013;28(3):196–202.CrossRefPubMed
18.
Ieiri I, et al. SLCO1B1 (OATP1B1, an uptake transporter) and ABCG2 (BCRP, an efflux transporter) variant alleles and pharmacokinetics of pitavastatin in healthy volunteers. Clin Pharmacol Ther. 2007;82(5):541–7.CrossRefPubMed
19.
Prueksaritanont T, et al. Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin Pharmacol. 2014;78(3):587–98.CrossRefPubMedPubMedCentral
20.
Li R, Barton HA, Maurer TS. Toward prospective prediction of pharmacokinetics in OATP1B1 genetic variant populations. CPT Pharmacomet Syst Pharmacol. 2014;3:e151.CrossRef
21.
Niemi M, et al. Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics. Pharmacogenet Genom. 2006;16(11):801–8.CrossRef
22.
Ieiri I, Higuchi S, Sugiyama Y. Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin Drug Metab Toxicol. 2009;5(7):703–29.CrossRefPubMed
23.
Ho RH, et al. Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics. 2007;17(8):647–56.CrossRefPubMedPubMedCentral
24.
Niemi M, et al. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics. 2004;14(7):429–40.CrossRefPubMed
25.
Choi MK, et al. Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors. Xenobiotica. 2011;41(1):24–34.CrossRefPubMed
26.
Deng JW, et al. The effect of SLCO1B1*15 on the disposition of pravastatin and pitavastatin is substrate dependent: the contribution of transporting activity changes by SLCO1B1*15. Pharmacogenet Genom. 2008;18(5):424–33.CrossRef
27.
Niemi M, Pasanen MK, Neuvonen PJ. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin Pharmacol Ther. 2006;80(4):356–66.CrossRefPubMed
28.
Riedmaier S, et al. Paraoxonase (PON1 and PON3) polymorphisms: impact on liver expression and atorvastatin-lactone hydrolysis. Front Pharmacol. 2011;2:41.CrossRefPubMedPubMedCentral
29.
Riedmaier S, et al. UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin Pharmacol Ther. 2010;87(1):65–73.CrossRefPubMed
30.
Birmingham BK, et al. Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect? Eur J Clin Pharmacol. 2015;71(3):341–55.CrossRefPubMed
31.
Kim KA, Joo HJ, Park JY. ABCG2 polymorphisms, 34G>A and 421C>A in a Korean population: analysis and a comprehensive comparison with other populations. J Clin Pharm Ther. 2010;35(6):705–12.CrossRefPubMed
32.
Nakanishi T, Tamai I. Genetic polymorphisms of OATP transporters and their impact on intestinal absorption and hepatic disposition of drugs. Drug Metab Pharmacokinet. 2012;27(1):106–21.CrossRefPubMed
33.
de Jong FA, et al. ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition. Clin Cancer Res. 2004;10(17):5889–94.CrossRefPubMed
34.
Mizuarai S, Aozasa N, Kotani H. Single nucleotide polymorphisms result in impaired membrane localization and reduced atpase activity in multidrug transporter ABCG2. Int J Cancer. 2004;109(2):238–46.CrossRefPubMed
35.
Zamber CP, et al. Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics. 2003;13(1):19–28.CrossRefPubMed
36.
Imai Y, et al. C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Mol Cancer Ther. 2002;1(8):611–6.PubMed
37.
Kobayashi D, et al. Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta. Drug Metab Dispos. 2005;33(1):94–101.CrossRefPubMed
38.
Pasanen MK, et al. Frequencies of single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in a Finnish population. Eur J Clin Pharmacol. 2006;62(6):409–15.CrossRefPubMed
39.
Sui SM, et al. Effect of OATP1B1 521T>C heterogenesis on pharmacokinetic characteristics of rosuvastatin in Chinese volunteers. Acta Pharm Sin. 2011;46(6):695–700.
40.
Lee E, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther. 2005;78(4):330–41.CrossRefPubMed
41.
Zhu J, et al. Effect of pitavastatin in different SLCO1B1 backgrounds on repaglinide pharmacokinetics and pharmacodynamics in healthy Chinese males. Pak J Pharm Sci. 2013;26(3):577–84.PubMed
42.
Nishizato Y, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003;73(6):554–65.CrossRefPubMed
43.
Choi JH, et al. Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans. Clin Pharmacol Ther. 2008;83(2):251–7.CrossRefPubMed
Metadata
Title
Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis
Authors
Rui Li
Hugh A. Barton
Publication date
01-04-2018
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 4/2018
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-017-0568-7

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