Urinary diazepam metabolite distribution in a chronic pain population.
Diazepam is often used as an adjuvant to pain therapy. Cytochrome P450 (CYP) 3A4 and 2C19 metabolize diazepam into the active metabolites: nordiazepam, temazepam and oxazepam. Owing to diazepam's side-effect profile, mortality risk and potential for drug-drug interactions with CYP 3A4 and/or CYP 2C19 inhibitors, urine drug testing (UDT) could be a helpful monitoring tool. This was a retrospective data analysis that evaluated urine specimens from pain management practices for the distribution of diazepam metabolites with and without CYP 3A4 and 2C19 inhibitors. Intersubject nordiazepam, temazepam and oxazepam geometric mean fractions were 0.16, 0.34 and 0.47, respectively. Intrasubject geometric mean fractions were 0.157, 0.311 and 0.494, respectively. Sex, but not age or urinary pH, had an effect on metabolite fractions. Methadone significantly increased temazepam and oxazepam urinary fractions via CYP3A4 inhibition, whereas fluoxetine and esomeprazole increased nordiazepam fractions via CYP2C19 inhibition. Although more studies are needed, these results suggest the viability of UDT for increased monitoring for therapy and possible drug-drug interactions.
1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego (UC San Diego), 9500 Gilman Drive, MC 0719, La Jolla, CA, USA.
Samantha
S
Luk
Rabia S
RS
Atayee
Joseph D
JD
Ma
Brookie M
BM
Best
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D059350:Chronic Pain / Q000188:drug therapy* / Q000652:urine; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003975:Diazepam / Q000008:administration & dosage* / Q000009:adverse effects / Q000652:urine*; D004347:Drug Interactions; D064098:Esomeprazole / Q000008:administration & dosage; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008691:Methadone / Q000008:administration & dosage; D003708:Nordazepam / Q000652:urine; D010076:Oxazepam / Q000652:urine; D012189:Retrospective Studies; D013048:Specimen Handling; D013693:Temazepam / Q000652:urine
D065692:Cytochrome P-450 CYP3A Inhibitors; D005473:Fluoxetine; D003708:Nordazepam; D010076:Oxazepam; D013693:Temazepam; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D064098:Esomeprazole; D003975:Diazepam; D008691:Methadone