Abstract
Repaglinide is type 2 short acting anti-diabetic drug which is primarily metabolized by CYP2C8 and CYP3A4 and is also a substrate of influx transporter OATP1B1. HIV drugs are potent inhibitors of CYP3A4 and OATP transporters. Several drug-drug interactions (DDIs) were noticed when protease inhibitors (PIs) coadministered with drugs metabolized by CYP3A4. The PIs are also potent mechanism based inhibitors, out which ritonavir is most potent. In the current study we evaluated in vitro (mouse and human liver microsomes) and in vivo DDIs of repaglinide with anti-HIV drugs. Out of the following tested drugs (Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Delavirdine, Maraviroc, Efavirenz, Nevirapine and Ketoconazole) Amprenavir (APV), Ritonavir (RTV) and Ketoconazole (KTZ) showed inhibition of OH-repaglinide formation in human and mouse liver microsomes. The positive reversible inhibitions were further tested for irreversible inhibitions where we didn’t observe any irreversible inhibitions. In vitro inhibitions were further evaluated in the in vivo pharmacokinetics (mouse) where repaglinide pharmacokinetics was altered by RTV and KTZ. The DDIs in both studies were very strong; the dose of repaglinide is reduced to 20 fold. In conclusion, there could be possible DDIs when RTV dosed with repaglinide; we have also demonstrated that mouse could be useful preclinical tool when used in conjunction with in vitro screening models for DDIs.
Highlights
People living with diabetes would reach 366 Vs 171 million by 2030, out of which 90 to 95% are type 2 diabetic patients
In a previous study in our lab we had seen that except indinavir all tested protease inhibitors (PIs) demonstrated irreversible inhibition of CYP3A4 (Ritonavir, Indinavir, Nelfinavir, Saquinavir and Amprenavir) and these results were in agreement with published results [3]
HIV drugs which are known CYP3A4 inhibitors and OATP inhibitors would alter pharmacokinetics of repaglinide. http://www.hiv-druginteractions.org published by liver pool university indicated some possible drug-drug interactions (DDIs) of anti-HIV drugs when repaglinide was coadministrated. They indicated that close monitoring or dose adjustment was required when repaglinide dosed with atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir
Summary
People living with diabetes would reach 366 Vs 171 million by 2030, out of which 90 to 95% are type 2 diabetic patients. Pharmacokinetic drug interactions were observed in repaglinide with drugs which are inhibitors of CYP3A4, CYP2C8 and transporter OATP1B1. Severe DDIs were observed when gemfibrozil was coadministered with repaglinide; an eight fold increase in repaglinide AUC was seen. This drug interaction was further enhanced with introduction of itraconazole. Http://www.hiv-druginteractions.org published by liver pool university indicated some possible DDIs of anti-HIV drugs when repaglinide was coadministrated. They indicated that close monitoring or dose adjustment was required when repaglinide dosed with atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir. KTZ was used as positive control for CYP3A4 inhibition in in vitro and in vivo
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