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Journal of Clinical Endocrinology & Metabolism Vol. 72, No. 4 755-760
doi:10.1210/jcem-72-4-755
Copyright © 1991 by the Endocrine Society.
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Inhibition of Peripheral Aromatization in the Male Cynomolgus Monkey by a Novel Nonsteroidal Aromatase Inhibitor (R 76713)*

ROBERT W. TUMAN, DAVID M. MORRIS, NATHANIEL H. WALLACE and CHARLES R. BOWDEN

Department of Biological Research, Endocrinology Group, Janssen Research Foundation Spring House, Pennsylvania 19477–0776

Address all correspondence and requests for reprints to: Dr. Robert W. Tuman, Endocrinology Group, Department of Biological Research, Janssen Research Foundation, Spring House, Pennsylvania 19477–0776.

R 76713 (6-[(4-chlorophenyl)(1-H-1,2,4-trizol-yl)methyl]1-H benzotriazole) is a highly potent and selective inhibitor of the aromatase enzyme both in vitro and in vivo. The ability of R 76713 to inhibit peripheral aromatization of androstenedione (A) to estrone (E1) in vivo was studied in male cynomolgus monkeys (Macaca fascicularis). Peripheral aromatization was measured using a primed constant infusion of [3H] A and [14C]E1 for 3.5 h. Blood samples, collected during the final hour of infusion, were analyzed for plasma radioactivity as infused and product steroids. MCRs, conversion ratios (CR), and percent conversion of A to E1 were calculated. R 76713 (0.03–10 µg/kg) or vehicle (10% hydroxypropyl-β-cyclodextrin) were administered iv 90 min before beginning the infusion of radiolabeled steroids. In vehicle-treated monkeys, the aromatization of A (mean ± SEM, 1.35 ± 0.11%) was similar to that previously reported for cynomolgus and rhesus monkeys, baboons, and humans. Aromatization of A, measured 4–5 h after injection of R 76713, was dose-dependently decreased from the control value by 87 ± 3%, 85 ± 2%, 61 ± 5%, and 33 ± 8% (all P < 0.05) at doses of 10.0, 3.0, 0.3, and 0.03 µg/kg, respectively, with an ID50 of 0.13 µg/kg, iv (95% confidence interval, 0.06–0.21). When measured 15–16 h after iv administration of 3.0 µg/kg R 76713, aromatization (0.55 ± 0.13%) was significantly inhibited by 53 ± 11% compared to that in control monkeys (1.16 ± 0.18%).

The CRs between androgens, the CRs between estrogens, and the MCRs of A and E1 were not significantly altered by R 76713 compared to those after vehicle treatment. R 76713 potently decreased peripheral conversion of androgen to estrogen in vivo in male cynomolgus monkeys and may be a useful therapeutic agent in treating estrogen-dependent diseases, including postmenopausal breast cancer. (J Clin Endocrinol Metab 72: 755–760, 1991)

* This work was presented in part at the Ninth International Symposium of the Journal of Steroid Biochemistry, Las Palmas, Spain, May 1989; at the 71st Annual Meeting of The Endocrine Society, Seattle, WA, June 1989; and at the 14th Meeting of the International Study Group on Steroid Hormones, Rome, Italy, November 1989.

Received July 23, 1990.







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Copyright © 1991 by The Endocrine Society