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Bioavailability and Pharmacokinetics of Dehydroepiandrosterone in the Cynomolgus Monkey

Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval) and Laval University, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Pr. Fernand Labrie, Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (Centre Hospitalier de l’Université Laval), 2705 Laurier Boulevard, Québec, Canada G1V 2G2. E-mail: fernand.labrie{at}crchul.ulaval.ca.

We have studied the pharmacokinetics of dehydroepiandrosterone (DHEA) administered orally (PO), iv, and during a continuous iv infusion in ovariectomized cynomolgus monkeys under suppression of adrenal DHEA secretion with dexamethasone. The glucocorticoid induced a rapid suppression of serum cortisol, DHEA, and DHEA-sulfate (DHEA-S) as well as their metabolites, thus permitting to use this model to study the pharmacokinetic parameters of DHEA and its metabolites without significant interference by endogenous steroid levels.

After a single 10 mg iv dose of DHEA, the metabolic clearance rate and terminal half-life of DHEA were 99.9 ± 9.1 liter/d and 4.5 ± 0.3 h, respectively. Following a 50-mg DHEA PO dose, systemic availability was only 3.1 ± 0.4%. As shown by their high conversion ratios, the major circulating metabolites of DHEA are DHEA-S, androsterone glucuronide, and androstane-3,17ß-diol-glucuronide. The conversion ratios of androst-5-ene-3ß,17ß-diol, testosterone, dihydrotestosterone, and androstenedione are, in comparison, small. No transformation to estrogens could be detected in the circulation after either iv or PO DHEA administration.

The present data indicate that DHEA is transformed predominantly into androgens in peripheral tissues in ovariectomized cynomolgus monkeys with minimal (androgens) or no (estrogens) release of the bioactive steroids in the circulation. Furthermore, the present study supports the importance of measuring circulating androgen glucuronide derivatives to assess hormonal exposure of peripheral tissues to androgens after DHEA administration.

This work was supported by the Canadian Institutes of Health Research.

Abbreviations: ADT-G, Androsterone glucuronide; AUC, area under the curve; BLQ, below the limit of quantification; C_max and C_min, maximum and minimum serum concentrations measured during the study period; CR, conversion ratio; DEX, dexamethasone; DHEA, dehydroepiandrosterone; DHEA-S, DHEA sulfate; DHT, dihydrotestosterone; 5-diol, androst-5-ene-3ß,17ß-diol; 4-dione, androstenedione; DMSO, dimethylsulfoxide; E₁, estrone; E₂, estradiol; MCR, metabolic clearance rate; OVX, ovariectomized or ovariectomy; PO, oral(ly); testo, testosterone; UGT, uridine diphosphate-glucuronosyltransferase.

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