Repaglinide‐gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Co-administration of gemfibrozil significantly increases the exposure of repaglinide.• CYP3A4 and CYP2C8 are important in the metabolism of repaglinide.• OATP1B1 polymorphism is an independent predictor of repaglinide pharmacokinetics.• Gemfibrozil and its O-glucuronide are CYP2C8 and OATP1B1 inhibitors. WHAT THIS STUDY ADDS• Acyl glucuronidation is a major metabolic pathway of repaglinide in vitro.• Gemfibrozil and its glucuronide inhibit the glucuronidation of repaglinide. • UGT1A1 is a major enzyme responsible for the glucuronidation of repaglinide. AIMTo further explore the mechanism underlying the interaction between repaglinide and gemfibrozil, alone or in combination with itraconazole. METHODSRepaglinide metabolism was assessed in vitro (human liver subcellular fractions, fresh human hepatocytes, and recombinant enzymes) and the resulting incubates were analyzed, by liquid chromatography-mass spectrometry (LC-MS) and radioactivity counting, to identify and quantify the different metabolites therein. Chemical inhibitors, in addition to a trapping agent, were also employed to elucidate the importance of each metabolic pathway. Finally, a panel of human liver microsomes (genotyped for UGT1A1*28 allele status) was used to determine the importance of UGT1A1 in the direct glucuronidation of repaglinide. RESULTSThe results of the present study demonstrate that repaglinide can undergo direct glucuronidation, a pathway that can possibly contribute to the interaction with gemfibrozil. For example, [ 3 H]-repaglinide formed glucuronide and oxidative metabolites (M2 and M4) when incubated with primary human hepatocytes. Gemfibrozil effectively inhibited (~78%) both glucuronide and M4 formation, but had a minor effect on M2 formation. Concomitantly, the overall turnover of repaglinide was also inhibited (~80%), and was completely abolished when gemfibrozil was co-incubated with itraconazole. These observations are in qualitative agreement with the in vivo findings. UGT1A1 plays a significant role in the glucuronidation of repaglinide. In addition, gemfibrozil and its glucuronide inhibit repaglinide glucuronidation and the inhibition by gemfibrozil glucuronide is time-dependent. CONCLUSIONSInhibition of UGT enzymes, especially UGT1A1, by gemfibrozil and its glucuronide is an additional mechanism to consider when rationalizing the interaction between repaglinide and gemfibrozil.

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…Antidiabetic Agents. The nonsulfonylurea insulin secretagogue repaglinide is metabolized primarily by CYP2C8 (Table 4) and CYP3A4, but it also undergoes direct glucuronidation by uridine-59-diphosphoglucuronosyltransferase (UGT) 1A1 (Bidstrup et al, 2003;Kajosaari et al, 2005a,b;Gan et al, 2010). In addition, there is in vitro data suggesting that aldehyde dehydrogenase is involved in its metabolism (Säll et al, 2012).…”

In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases

“…The authors estimated CYP2C8 to account for ;80% of montelukast metabolism in humans (Karonen et al, 2010(Karonen et al, , 2012 and recommended montelukast as a selective CYP2C8 probe of activity in vivo. However, gemfibrozil inhibits multiple drug disposition proteins other than CYP2C8 to varying degree (Wen et al, 2001;Prueksaritanont et al, 2002;Shitara et al, 2004;Noe et al, 2007;Mougey et al, 2009;Gan et al, 2010), and it is possible the observed in vivo effect of gemfibrozil may have been mediated in part through inhibition of other pathways in addition to the known inhibition of CYP2C8. Consistent with a previous study showing inhibition of expressed UGT1A3 by gemfibrozil (Gan et al, 2010), our in vitro data show modest inhibition of montelukast glucuronidation in HLMs, although the potency of this inhibition appears too low to explain the effect of gemfibrozil on montelukast exposure in vivo.…”

Physiologically Based Pharmacokinetic Prediction of Telmisartan in Human

“…When rifamycin SV was present to inhibit active uptake clearance ( Fig. 1), an inhibited metabolic clearance (F inhibition  CL int, u, met ) was used to represent potential inhibition of glucuronidation by rifamycin SV observed in the current study and a previous study (Gan et al, 2010): …”