Metabolism of an anabolic androgenic steroid, oxymetholone by human cytochrome P450s

D. L. Thacker, I. Wainer, C. Lerch, K. Fried, D. A. Flockhart

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

We investigated the human metabolism of oxymetholone (OXY) in human liver microsomes and recombinant human cytochrome P450 (CYP450) isoforms. OXY is a 17α-alkylated anabolic androgenic steroid under investigation for the treatment of HIV, cancer wasting syndromes and male osteoporosis. No data currently exist on the CYP450 isoforms involved in the human metabolism of OXY and so it is not currently possible to predict likely drug interactions that might result in toxicity or lack of efficacy. OXY was able to inhibit the metabolism of probe drugs for CYP450 2D6 (dextromethorphan [25μM] to dextrorphan), CYP450 3A (dextromethorphan [ 125μM] to 3-methoxymorphian) with IC50 values of 389±31 μM and 300±195 μM. CYP450 2C9 (tolbutamide to 4-OH-tolbutamide) was inhibited with an IC50 of 67.5 ± 10.6 μM. also CYP450 2C19 (omeprazole to 5-OH-omeprazole) was inhibited with an IC50 of 206 μM. When OXY (0 μM - 50 μM) was incubated with ritonavir, a known CYP450 3A substrate, there was weak competitive inhibition of ritonavir metabolism (Ki = 142 μM). When OXY was incubated with human liver microsomes or recombinant CYP450 enzymes, OXY metabolism occurred in a non-NADPH dependant manner, indicating that the primary route of OXY metabolism is not via CYP450, consistent with the metabolism of other androgenic steroids such as testosterone. We conclude that OXY interacts with human cytochrome P450s 2D6, 3A, 2C9 and 2C19, but is unlikely to cause clinically significant interactions at therapeutic doses.

Original languageEnglish (US)
Pages (from-to)136
Number of pages1
JournalClinical Pharmacology and Therapeutics
Volume65
Issue number2
StatePublished - 1999
Externally publishedYes

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Oxymetholone
Testosterone Congeners
Cytochromes
Cytochrome P-450 Enzyme System
Inhibitory Concentration 50
Dextromethorphan
Cytochrome P-450 CYP3A
Ritonavir
Tolbutamide
Omeprazole
Liver Microsomes
HIV Wasting Syndrome
Protein Isoforms
Dextrorphan
Cytochrome P-450 CYP2D6
Drug Interactions
Osteoporosis
Testosterone
Steroids

ASJC Scopus subject areas

  • Pharmacology

Cite this

Thacker, D. L., Wainer, I., Lerch, C., Fried, K., & Flockhart, D. A. (1999). Metabolism of an anabolic androgenic steroid, oxymetholone by human cytochrome P450s. Clinical Pharmacology and Therapeutics, 65(2), 136.

Metabolism of an anabolic androgenic steroid, oxymetholone by human cytochrome P450s. / Thacker, D. L.; Wainer, I.; Lerch, C.; Fried, K.; Flockhart, D. A.

In: Clinical Pharmacology and Therapeutics, Vol. 65, No. 2, 1999, p. 136.

Research output: Contribution to journalArticle

Thacker, DL, Wainer, I, Lerch, C, Fried, K & Flockhart, DA 1999, 'Metabolism of an anabolic androgenic steroid, oxymetholone by human cytochrome P450s', Clinical Pharmacology and Therapeutics, vol. 65, no. 2, pp. 136.
Thacker, D. L. ; Wainer, I. ; Lerch, C. ; Fried, K. ; Flockhart, D. A. / Metabolism of an anabolic androgenic steroid, oxymetholone by human cytochrome P450s. In: Clinical Pharmacology and Therapeutics. 1999 ; Vol. 65, No. 2. pp. 136.
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