Journal of Andrology Testis Workshop 2009
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Published-Ahead-of-Print September 18, 2008, DOI:10.2164/jandrol.108.004994

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Adjudin Targeting Rabbit Germ Cell Adhesion as a Male Contraceptive: a Pharmacokinetic Study

Guo-xin Hu , Lu-Feng Hu , Dai-Zheng Yang , Jun-Wei Li , Guo-Rong Chen , Bing-Bing Chen , Dolores D. Mruk , Michele Bonanomi , Bruno Silvestrini , C. Yan Cheng , and Ren-Shan Ge *

* To whom correspondence should be addressed. E-mail: r_ge{at}yahoo.com.

Adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (formerly called AF-2364), has been shown to inhibit spermatogenesis by disrupting anchoring junctions at the Sertoli-germ cell interface. This, in turn, leads to germ cell loss from the seminiferous epithelium, and transient infertility. Its efficacy of inhibiting spermatogenesis, the recovery of spermatogenesis after cessation of the drug, and side effects were examined in adult male Japanese rabbits. The pharmacokinetic profiles of adjudin in rabbits after oral administration and after intravenous injection were compared. Rabbits received 25 mg/kg adjudin once weekly for 4 consecutive weeks either by intravenous injection or by gavage. Vehicle-treated rabbits were used as controls. 1, 2, 3, 4 and 8 weeks after treatment, testes were removed for microscopic examination to assess the status of spermatogenesis. Four weeks after intravenous cessation of adjudin, the recovery of spermatogenesis was also examined. Bloods were withdrawn after first administration to measure plasma concentrations of adjudin by HPLC. Four weeks after intravenous treatment, examination of testis sections showed rapid exfoliation of elongated/elongating spermatids and the large multinucleated cells; >95% germ cells were absent. The intravenous treatment showed much severe disturbance of spermatogenesis compared to gavage treatment, which was correlated with bioavailability of the drug. The areas under curves (AUCs) for intravenous injection or gavage were 20.11 ± 1.90 and 2.23 ± 0.45 mg.h.L-1, respectively. These results illustrate the potential of adjudin as a male contraceptive and the efficacy is associated with the bioavailability of the drug.


Key words: Contraception • Fertility • Testis






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