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The In Vivo Response of Novel Buprenorphine Metabolites, M1 and M3, to Antiretroviral Inducers and Inhibitors of Buprenorphine Metabolism
Author(s) -
Moody David E.,
Chang Yan,
Huang Wei,
McCanceKatz Elinore F.
Publication year - 2009
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2009.00432.x
Subject(s) - ritonavir , lopinavir , pharmacology , buprenorphine , cyp3a , chemistry , metabolite , nelfinavir , efavirenz , in vivo , urine , metabolism , medicine , biology , cytochrome p450 , biochemistry , viral load , human immunodeficiency virus (hiv) , immunology , receptor , microbiology and biotechnology , opioid , antiretroviral therapy
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.