Effects of the genetic variants of organic cation transporters 1 and 3 on the pharmacokinetics of metformin in Jordanians
-
Nancy Hakooz
,
Yazun Bashir Jarrar
Abstract
Background:
Human response to the antidiabetic metformin is influenced by some factors, such as genetic variants in the SLC22A genes. This study aimed to determine the frequency of main SLC22A1 and SLC22A3 genetic variants and their influence on metformin pharmacokinetics among healthy unrelated Arab Jordanians.
Patients and methods:
The SLC22A1 and SLC22A3 genes were genotyped by DNA sequencing of exons 1, 3, 7, and 9 in the SLC22A1 gene and exons 6, 7, and 9 in the SLC22A3 gene. Then, a clinical pharmacokinetic study was conducted on 26 healthy volunteers. The pharmacokinetic parameters were calculated using non-compartmental model analysis. The study was an open-label, randomized study with single 1000 mg metformin administration.
Results:
Results showed that volunteers with SLC22A3 rs8187722 variant had higher (χ2, p<0.05) metformin Cmax and AUC values than the wild SLC22A3 volunteers, whereas T½ and Kel were not affected. In addition, volunteers with the heterozygote SLC22A3 rs2292334 variant had significantly higher (χ2, p<0.05) metformin Cmax and AUC and lower Kel values than the wild-type SLC22A3 genotype.
Conclusions:
The SLC22A3 rs8187722 and rs2292334 genetic variants affected metformin pharmacokinetics among a clinical sample of Jordanians. The findings may increase our understanding of the inter-individual and inter-ethnic variations in metformin response.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This work was supported by a grant of the Deanship of Academic Research at The University of Jordan.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Reitman ML, Schadt EE. Pharmacogenetics of metformin response: a step in the path toward personalized medicine. J Clin Invest 2007;117:1226–9.10.1172/JCI32133Search in Google Scholar PubMed PubMed Central
2. Motohashi H, Inui K. Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AAPS J 2013;15:581–8.10.1208/s12248-013-9465-7Search in Google Scholar PubMed PubMed Central
3. He X, Garza D, Nigam SK, Chang G. Multispecific organic cation transporter 1 (OCT1) from bos taurus has high affinity and slow binding kinetics towards prostaglandin E2. PLoS One 2016;11:1–12.10.1371/journal.pone.0152969Search in Google Scholar PubMed PubMed Central
4. Zhang S, Lovejoy KS, Shima JE, Lagpacan LL, Shu Y, Lapuk A, et al. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res 2006;66:8847–57.10.1158/0008-5472.CAN-06-0769Search in Google Scholar PubMed PubMed Central
5. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 2008;83:273–80.10.1038/sj.clpt.6100275Search in Google Scholar PubMed PubMed Central
6. Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 2002;302:510–5.10.1124/jpet.102.034140Search in Google Scholar PubMed
7. Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. OCT1 polymorphism is associated with response and survival time in anti-Parkinsonian drug users. Neurogenetics 2011;12:79–82.10.1007/s10048-010-0254-5Search in Google Scholar PubMed PubMed Central
8. Chen L, Takizawa M, Chen E, Schlessinger A, Segenthelar J, Choi JH, et al. Genetic polymorphisms in organic cation transporter 1 (OCT1) in Chinese and Japanese populations exhibit altered function. J Pharmacol Exp Ther 2010;335:42–50.10.1124/jpet.110.170159Search in Google Scholar PubMed PubMed Central
9. Semiz S, Dujic T, Causevic A. Pharmacogenetics and personalized treatment of type 2 diabetes. Biochem Med (Zagreb) 2013;23:154–71.10.11613/BM.2013.020Search in Google Scholar PubMed
10. Tzvetkov MV, Vormfelde SV, Balen D, Meineke I, Schmidt T, Sehrt D, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 2009;86:299–306.10.1038/clpt.2009.92Search in Google Scholar PubMed
11. Chen L, Pawlikowski B, Schlessinger A, More SS, Stryke D, Johns SJ, et al. Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenet Genomics 2010;20:687–99.10.1097/FPC.0b013e32833fe789Search in Google Scholar PubMed
12. Seitz T, Stalmann R, Dalila N, Chen J, Pojar S, Dos Santos Pereira JN, et al. Global genetic analyses reveal strong inter-ethnic variability in the loss of activity of the organic cation transporter OCT1. Genome Med 2015;7:56.10.1186/s13073-015-0172-0Search in Google Scholar PubMed
13. Yoon H, Cho HY, Yoo HD, Kim SM, Lee YB. Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects. AAPS J 2013;15:571–80.10.1208/s12248-013-9460-zSearch in Google Scholar PubMed
14. Vlahov V, Thyroff-Friesinger U, Koytchev R, Bakracheva N, Gatchev E. Bioequivalence studies with metformin: comparability of reference tablets from different origins. Int J Clin Pharmacol Ther 2005;43:457–62.10.5414/CPP43457Search in Google Scholar PubMed
15. ICH harmonized tripartite guideline: Guideline for Good Clinical Practice. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. J Postgrad Med 2001;47:45–50.Search in Google Scholar PubMed
16. Kar M, Choudhury PK. HPLC method for estimation of metformin hydrochloride in formulated microspheres and tablet dosage form. Indian J Pharm Sci 2009;71:318–20.10.4103/0250-474X.56031Search in Google Scholar PubMed
17. Wu X, Huang W, Ganapathy ME, Wang H, Kekuda R, Conway SJ, et al. Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney. Am J Physiol Renal Physiol 2000;279:F449–58.10.1152/ajprenal.2000.279.3.F449Search in Google Scholar PubMed
18. Jarrar YB, Ismail S, Irshaid YM. N-Acetyltransferase-2 (NAT2) genotype frequency among Jordanian volunteers. Int J Clin Pharmacol Ther 2010;48:688–94.10.5414/CPP48688Search in Google Scholar PubMed
19. Ossaily S, Zgheib NK. The pharmacogenetics of drug metabolizing enzymes in the Lebanese population. Drug Metabol Drug Interact 2014;29:81–90.10.1515/dmdi-2013-0058Search in Google Scholar PubMed
20. Sanchez-Velasco P, Karadsheh NS, Garcia-Martin A, Ruiz de Alegria C, Leyva-Cobian F. Molecular analysis of HLA allelic frequencies and haplotypes in Jordanians and comparison with other related populations. Hum Immunol 2001;62:901–9.10.1016/S0198-8859(01)00289-0Search in Google Scholar PubMed
21. McLellan RA, Oscarson M, Seidegard J, Evans DA, Ingelman-Sundberg M. Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics 1997;7:187–91.10.1097/00008571-199706000-00003Search in Google Scholar PubMed
22. Zihlif M, Imraish A, Irshaid YM. Frequency of certain single-nucleotide polymorphisms and duplication of CYP2D6 in the Jordanian population. Genet Test Mol Biomarkers 2012;16: 1201–5.10.1089/gtmb.2012.0122Search in Google Scholar PubMed
23. Ozer M, Demirci Y, Hizel C, Sarikaya S, Karalti I, Kaspar C, et al. Impact of genetic factors (CYP2C9, VKORC1 and CYP4F2) on warfarin dose requirement in the Turkish population. Basic Clin Pharmacol Toxicol 2013;112:209–14.10.1111/bcpt.12024Search in Google Scholar PubMed
24. Alsmadi O, John SE, Thareja G, Hebbar P, Antony D, Behbehani K, et al. Genome at juncture of early human migration: a systematic analysis of two whole genomes and thirteen exomes from Kuwaiti population subgroup of inferred Saudi Arabian tribe ancestry. PLoS One 2014;9:1–19.10.1371/journal.pone.0099069Search in Google Scholar PubMed PubMed Central
25. Hakooz N, Alzubiedi S, Yousef AM, Arafat T, Dajani R, Ababneh N, et al. UDP-glucuronosyltransferase 1A4 (UGT1A4) polymorphisms in a Jordanian population. Mol Biol Rep 2012;39:7763–8.10.1007/s11033-012-1615-ySearch in Google Scholar PubMed
26. Piel FB, Adamkiewicz TV, Amendah D, Williams TN, Gupta S, Grosse SD. Observed and expected frequencies of structural hemoglobin variants in newborn screening surveys in Africa and the Middle East: deviations from Hardy-Weinberg equilibrium. Genet Med 2016;18:265–74.10.1038/gim.2015.143Search in Google Scholar PubMed PubMed Central
27. The International HapMap Project. Opinion: integrating ethics and science in the international HapMap project. Nature 2003;426:789–96.10.1038/nature02168Search in Google Scholar PubMed
28. Jarrar YB, Cha EY, Seo KA, Ghim JL, Kim HJ, Kim DH, et al. Determination of major UDP-glucuronosyltransferase enzymes and their genotypes responsible for 20-HETE glucuronidation. J Lipid Res 2014;55:2334–42.10.1194/jlr.M051169Search in Google Scholar PubMed PubMed Central
29. Stocker SL, Morrissey KM, Yee SW, Castro RA, Xu L, Dahlin A, et al. The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther 2013;93:186–94.10.1038/clpt.2012.210Search in Google Scholar PubMed PubMed Central
30. Cho SK, Chung JY. The MATE1 rs2289669 polymorphism affects the renal clearance of metformin following ranitidine treatment. Int J Clin Pharmacol Ther 2016;54:253–62.10.5414/CP202473Search in Google Scholar PubMed
31. Kirchheiner J, Ufer M, Walter EC, Kammerer B, Kahlich R, Meisel C, et al. Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers. Pharmacogenetics 2004;14:19–26.10.1097/00008571-200401000-00002Search in Google Scholar PubMed
32. Kinzig-Schippers M, Tomalik-Scharte D, Jetter A, Scheidel B, Jakob V, Rodamer M, et al. Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Antimicrob Agents Chemother 2005;49:1733–8.10.1128/AAC.49.5.1733-1738.2005Search in Google Scholar PubMed PubMed Central
©2017 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Original Articles
- Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration
- Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats
- Imatinib quantification in human serum with LC-MS3 as an effective way of protein kinase inhibitor analysis in biological matrices
- Preliminary study of the association between the elimination parameters of phenytoin and phenobarbital
- Effects of the genetic variants of organic cation transporters 1 and 3 on the pharmacokinetics of metformin in Jordanians
- Short Communications
- Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations
- Need for pharmacogenetic studies on the prevalence of MTHFR mutations in Puerto Ricans and Hispanics
Articles in the same Issue
- Frontmatter
- Original Articles
- Genotyping and phenotyping of CYP2D6 and CYP3A isoenzymes in patients with alcohol use disorder: correlation with haloperidol plasma concentration
- Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats
- Imatinib quantification in human serum with LC-MS3 as an effective way of protein kinase inhibitor analysis in biological matrices
- Preliminary study of the association between the elimination parameters of phenytoin and phenobarbital
- Effects of the genetic variants of organic cation transporters 1 and 3 on the pharmacokinetics of metformin in Jordanians
- Short Communications
- Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations
- Need for pharmacogenetic studies on the prevalence of MTHFR mutations in Puerto Ricans and Hispanics
