CYP2C9 and OATP1B1 genetic polymorphisms affect the metabolism and transport of glimepiride and gliclazide

Abstract

The therapeutic use of glimepiride and gliclazide shows substantial inter-individual variation in pharmacokinetics and pharmacodynamics in human populations, which might be caused by genetic differences among individuals. The aim of this study was to assess the effect of CYP2C9 and OATP1B1 genetic polymorphisms on the metabolism and transport of glimepiride and gliclazide. The uptake of glimepiride and gliclazide was measured in OATP1B1*1a, *5 and *15-HEK293T cells, and their metabolism was measured using CYP2C9*1, *2 and *3 recombinase by LC-MS. Glimepiride in OATP1B1*1a, *5 and *15-HEK293T cells had Vmax values of 155 ± 18.7, 80 ± 9.6, and 84.5 ± 8.2 pmol/min/mg, while gliclazide had Vmax values of 15.7 ± 4.6, 7.2 ± 2.5, and 8.7 ± 2.4 pmol/min/mg, respectively. The clearance of glimepiride and gliclazide in OATP1B1*5 and *15 was significantly reduced compared to the wild-type. Glimepiride in the presence of CYP2C9*1, *2 and *3 recombinase had Vmax values of 21.58 ± 7.78, 15.69 ± 5.59, and 9.17 ± 3.03 nmol/min/mg protein, while gliclazide had Vmax values of 15.73 ± 3.11, 10.53 ± 4.06, and 6.21 ± 2.94 nmol/min/mg protein, respectively. The clearance of glimepiride and gliclazide in CYP2C9*2 and *3 was significantly reduced compared to the wild-type. These findings collectively indicate that OATP1B1*5 and *15 and CYP2C9*2 and *3 have a significant effect on the transport and metabolism of glimepiride and gliclazide.

Hepatic Transcript Profiles of Cytochrome P450 Genes Predict Sex Differences in Drug Metabolism

“…Eleven drugs were chosen that represented several drug classes and were metabolized by each of the sex-biased Cyps. Though the Cyp-drug association for these 11 drugs was initially obtained from PharmaPendium, a survey of literature reports allowed us to confirm such association, namely, azelastine (Imai et al, 1999), buspirone (Zhu et al, 2005), doxorubicin (Kivisto et al, 1995), fentanyl (Lotsch et al, 2013), glimepiride (Suzuki et al, 2006;Yang et al, 2018), irinotecan (Mathijssen et al, 2001), phenytoin (Franco and Perucca, 2015), pravastatin (Williams and Feely, 2002), tamsulosin (Franco-Salinas et al, 2010), tazarotene (Attar et al, 2003), and terfenadine (Ling et al, 1995) were mainly metabolized by the Cyp as indicated in the PharmaPendium. The metabolism of these drugs was evaluated in primary hepatocytes derived from the livers of adult male and female F344 rats.…”

OATP1B3 (699G>A) and CYP2C9*2, *3 significantly influenced the transport and metabolism of glibenclamide and glipizide

“…OATP and CYP2C9 play a vital role in drug disposition and often exhibit gene polymorphisms that significantly affect the transport and metabolism of many clinical drugs 4–6 . We have demonstrated that OATP1B1*5 and *15 and CYP2C9*2 and *3 have a significant effect on the transport and metabolism of glimepiride and gliclazide 7 .…”

Transport of salvianolic acid B via the human organic anion transporter 1B1 in the liver

“…Michaelis–Menten kinetics were applied to calculate the values of Vmax and Km. Michaelis–Menten equation: V = Vmax [S]/([Km + [S]), where V is the uptake velocity of the substrate (picomoles per milligram of protein per minute), Vmax is the maximum velocity (picomoles per milligram of protein per minute), [S] is the substrate concentration in the medium (micromolar), and Km is the Michaelis constant (micromolar; Yang et al, ). The protein concentration of each sample was determined using the bicinchoninic acid (BCA) Protein Assay Kit.…”