The in vivo response of novel buprenorphine metabolites, M1 and M3, to antiretroviral inducers and inhibitors of buprenorphine metabolism.
Buprenorphine metabolism was recently expanded by in vitro identification of a number of hydroxylated metabolites. The identification of two, M1 and M3, in urine suggests that they may be quantitatively significant metabolites. To further understand the in vivo regulation of this mode of metabolism, we evaluated 24-hr urine from subjects (10 per treatment group) on buprenorphine alone or with the antiretroviral agents: efavirenz, delavirdine, nelfinavir, ritonavir, and lopinavir/ritonavir. Quantitative analysis for buprenorphine and traditional metabolites and semi-quantitative analysis of M1 and M3 in urine were performed by liquid chromatography-electrospray ionization-tandem mass spectrometry. The renal clearance of buprenorphine and traditional metabolites were similar for all treatments except for lopinavir/ritonavir, suggesting that urine amounts of M1 and M3 would adequately reflect systemic changes (except lopinavir/ritonavir). Efavirenz decreased M1 and increased M3 consistent with its ability to induce cytochrome P450 (CYP) 3A. Delavirdine increased M1 and decreased M3 consistent with its ability to inhibit CYP3A. Both nelfinavir and ritonavir decreased both M1 and M3, consistent with their ability to inhibit CYP3A and 2C8. These results provide further information on the in vivo response of novel secondary metabolites of buprenorphine to metabolic inhibitors and inducers.
Moody
David E
DE
Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, UT 84108, USA. david.moody@utah.edu
Chang
Yan
Y
Huang
Wei
W
McCance-Katz
Elinore F
EF
D000701:Analgesics, Opioid / Q000378:metabolism*; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000502:physiology; D002047:Buprenorphine / Q000378:metabolism*; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000502:physiology; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism
D000701:Analgesics, Opioid; D044966:Anti-Retroviral Agents; D002047:Buprenorphine; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human