SpringerLink
Log in

Gender-Related Differences in the Expression of Organic Cation Transporter 2 and its Role in Urinary Excretion of Metformin in Rats

  • Original Paper
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Organic cation transporter 2 (rOCT2) and multidrug and toxin extrusion protein 1 (rMATE1) are mainly expressed in rat renal proximal tubules and mediate urinary excretion of cationic drugs, such as metformin. Accumulated evidence indicated that renal rOCT2 expression in male rats is much higher than that of female rats. However, it is unclear whether the gender-related differences in rOCT2 expression between male and female rats can affect the urinary excretion of metformin. The aim of this study was to investigate the effect of gender on the pharmacokinetics of metformin and to clarify the effect of gender-related differences on renal rOCT2 expression and its role in urinary excretion of metformin. Renal rOCT2 levels, but not rOCT1 and rMATE1, were significantly lowered in female rats when compared to that of male rats (P < 0.01), while the pharmacokinetic parameters, i.e., AUC0→t, t 1/2, CL/F, and cumulative urinary excretion of metformin, did not show any significant differences between female and male rats following oral administration of metformin at l00 mg/kg (P > 0.05). However, when metformin was orally administered at the dose of 500 mg/kg, the cumulative urinary excretion and renal tissue-to-plasma concentration ratio of metformin in female rats (26,689 ± 1266 μg and 2.96 ± 0.47 mL/g, respectively) were markedly lowered compared to that of male rats (32,949 ± 1384 μg and 4.20 ± 0.31 mL/g, respectively), and the plasma concentration of metformin in female rats (55.9 ± 4.5 μg/mL) was significantly increased compared to that of male rats (43.5 ± 3.1 μg/mL) at 2 h after oral administration. These results indicated that effect of gender-related differences on renal rOCT2 expression indeed contributes to the decreased urinary excretion of metformin in female rats when metformin was administered at relatively high doses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Thailand)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gleiter CH, Gundert-Remy U. Gender differences in pharmacokinetics. Eur J Drug Metab Pharmacokinet. 1996;21(2):123–8.

    Article  CAS  PubMed  Google Scholar 

  2. Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs. 1995;50(2):222–39.

    Article  CAS  PubMed  Google Scholar 

  3. Tanaka E. Gender-related differences in pharmacokinetics and their clinical significance. J Clin Pharm Ther. 1999;24(5):339–46.

    Article  CAS  PubMed  Google Scholar 

  4. Franconi F, Brunelleschi S, Steardo L, Cuomo V. Gender differences in drug responses. Pharmacol Res. 2007;55(2):81–95.

    Article  CAS  PubMed  Google Scholar 

  5. Meibohm B, Beierle I, Derendorf H. How important are gender differences in pharmacokinetics? Clin Pharmacokinet. 2002;41(5):329–42.

    Article  CAS  PubMed  Google Scholar 

  6. Bebawy M, Chetty M. Gender differences in p-glycoprotein expression and function: effects on drug disposition and outcome. Curr Drug Metab. 2009;10(4):322–8.

    Article  CAS  PubMed  Google Scholar 

  7. Buckley DB, Klaassen CD. Tissue- and gender-specific mRNA expression of UDP-glucuronosyltransferases (UGTs) in mice. Drug Metab Dispos. 2007;35(1):121–7.

    Article  CAS  PubMed  Google Scholar 

  8. Morris ME, Lee HJ, Predko LM. Gender differences in the membrane transport of endogenous and exogenous compounds. Pharmacol Rev. 2003;55(2):229–40.

    Article  CAS  PubMed  Google Scholar 

  9. Ou-Yang DS, Huang SL, Wang W, **e HG, Xu ZH, Shu Y, Zhou HH. Phenotypic polymorphism and gender-related differences of CYP1A2 activity in a Chinese population. Br J Clin Pharmacol. 2000;49(2):145–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol. 2001;2(6):349–51.

    Article  CAS  PubMed  Google Scholar 

  11. Koepsell H. Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci. 2004;25(7):375–81.

    Article  CAS  PubMed  Google Scholar 

  12. Koepsell H, Endou H. The SLC22 drug transporter family. Pflugers Arch. 2004;447(5):666–76.

    Article  CAS  PubMed  Google Scholar 

  13. Yonezawa A, Inui K. Organic cation transporter OCT/SLC22A and H(+)/organic cation antiporter MATE/SLC47A are key molecules for nephrotoxicity of platinum agents. Biochem Pharmacol. 2011;81(5):563–8.

    Article  CAS  PubMed  Google Scholar 

  14. Li X, Zhang N, Li Y, Shi Y, Li D, **e Y, Ming J. Effects of metformin and rosiglitazone on peripheral insulin resistance and beta-cell function in obesity: a double-blind, randomized, controlled study. J Int Med Res. 2011;39(2):358–65.

    Article  CAS  PubMed  Google Scholar 

  15. Ou HY, Cheng JT, Yu EH, Wu TJ. Metformin increases insulin sensitivity and plasma beta-endorphin in human subjects. Horm Metab Res. 2006;38(2):106–11.

    Article  CAS  PubMed  Google Scholar 

  16. Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50(2):81–98.

    Article  CAS  PubMed  Google Scholar 

  17. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 1996;30(5):359–71.

    Article  CAS  PubMed  Google Scholar 

  18. Kimura N, Masuda S, Tanihara Y, Ueo H, Okuda M, Katsura T, Inui K. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005;20(5):379–86.

    Article  CAS  PubMed  Google Scholar 

  19. Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics. 2008;9(4):415–22.

    Article  CAS  PubMed  Google Scholar 

  20. Urakami Y, Nakamura N, Takahashi K, Okuda M, Saito H, Hashimoto Y, Inui K. Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett. 1999;461(3):339–42.

    Article  CAS  PubMed  Google Scholar 

  21. Urakami Y, Okuda M, Saito H, Inui K. Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett. 2000;473(2):173–6.

    Article  CAS  PubMed  Google Scholar 

  22. Lickteig AJ, Cheng X, Augustine LM, Klaassen CD, Cherrington NJ. Tissue distribution, ontogeny and induction of the transporters multidrug and toxin extrusion (MATE) 1 and MATE2 mRNA expression levels in mice. Life Sci. 2008;83(1–2):59–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ito S, Kusuhara H, Yokochi M, Toyoshima J, Inoue K, Yuasa H, Sugiyama Y. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug–drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther. 2012;340(2):393–403.

    Article  CAS  PubMed  Google Scholar 

  24. Li Q, Guo D, Dong Z, Zhang W, Zhang L, Huang S-M, Polli JE, Shu Y. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs). Toxicol Appl Pharmacol. 2013;273(1):100–9.

    Article  CAS  PubMed  Google Scholar 

  25. Konig J, Zolk O, Singer K, Hoffmann C, Fromm MF. Double-transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: determinants of uptake and transcellular translocation of organic cations. Br J Pharmacol. 2011;163(3):546–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lepist EI, Zhang X, Hao J, Huang J, Kosaka A, Birkus G, Murray BP, Bannister R, Cihlar T, Huang Y, Ray AS. Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat. Kidney Int. 2014;86(2):350–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Strobel J, Muller F, Zolk O, Endress B, Konig J, Fromm MF, Maas R. Transport of asymmetric dimethylarginine (ADMA) by cationic amino acid transporter 2 (CAT2), organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1). Amino Acids. 2013;45(4):989–1002.

    Article  CAS  PubMed  Google Scholar 

  28. Jonker JW, Wagenaar E, Van Eijl S, Schinkel AH. Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol. 2003;23(21):7902–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, The First Hospital of Lanzhou University, No. 1 Donggangxi Road, Chengguan District, Lanzhou, Gansu, 730000, China

    Yan-rong Ma, Hong-yan Qin, Yong-wen **, **g Huang, Miao Han, **ng-dong Wang, Guo-qiang Zhang, Yan Zhou, Zhi Rao & **n-an Wu

  2. School of Pharmacy Lanzhou University, Lanzhou, 730000, China

    Yan-rong Ma, Yong-wen **, **g Huang, Miao Han & **ng-dong Wang

Authors
  1. Yan-rong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong-yan Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-wen **
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. **g Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Miao Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. **ng-dong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guo-qiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhi Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. **n-an Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to **n-an Wu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, Yr., Qin, Hy., **, Yw. et al. Gender-Related Differences in the Expression of Organic Cation Transporter 2 and its Role in Urinary Excretion of Metformin in Rats. Eur J Drug Metab Pharmacokinet 41, 559–565 (2016). https://doi.org/10.1007/s13318-015-0278-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-015-0278-1

Keywords

Search

Navigation