Presented at the 2012 AAPM Annual Meeting « Back

Effect of Cytochrome P450 (CYP) 2C19 Inhibitors on the Distribution of Urinary Diazepam Metabolites in Patients with Chronic Pain

Samantha O. Luk, BS, sluk@ucsd.edu¹, Rabia S. Atayee, PharmD BCPS², Joseph D. Ma, PharmD³, Brookie M. Best, PharmD MAS⁴, Amadeo J. Pesce, PhD DABCC⁵, (1) UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, California, (2) UCSD Skaggs School of Pharmacy, La Jolla, California, (3) Pharmacy, La Jolla, California, (4) UC San Diego, La Jolla, California, (5) Millennium Research Institute, San Diego, California

Background: Diazepam is used as an adjuvant to opioid therapy for pain-related anxiety. It is metabolized by cytochrome P450 (CYP) 2C19 into nordiazepam and CYP 3A4 into temazepam. Both metabolites are further metabolized to oxazepam. In previous studies, CYP 2C19 inhibitors increase diazepam plasma concentrations and cause significant clinical effects. However, the effect on urinary diazepam metabolites is not known. Methods: This was a retrospective analysis of deidentified urinary excretion data from testing at Millennium Laboratories of urine specimens collected from 2008 to 2011. This study was granted IRB-exempt status by the UCSD Human Research Protection Program. Two-sample t-tests and analyses were conducted on subjects reported to be on diazepam and not any of its metabolites. Results: From 20,614 subjects on diazepam and not on any diazepam metabolites, there were 1,770 subjects concurrently on CYP 2C19 inhibitors as compared to 18,844 subjects not concurrently on CYP2C19 inhibitors. Subjects taking diazepam and a CYP 2C19 inhibitor had a 10.4% decrease in the nordiazepam fraction (p < 0.00001), a 5.4% increase in the temazepam fraction (p < 0.00001) and no change in the oxazepam fraction. Conclusion: As expected, the nordiazepam fraction decreased and the temazepam fraction increased due to CYP 2C19 inhibition. This may be due to a shift in diazepam metabolism through the CYP 3A4 pathway. The fraction of oxazepam did not change in the presence of a CYP 2C19 inhibitor, suggesting that CYP 3A4 can compensate for CYP 2C19 inhibition.

Funding: An unrestricted grant was given to the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences to fund the summer internships by Millennium Laboratories, Inc.