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Inhibition of Peripheral Aromatization in the Male Cynomolgus Monkey by a Novel Nonsteroidal Aromatase Inhibitor (R 76713)^*

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.