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

GUO-RONG CHEN

BING-BING CHEN^*,

DOLORES D. MRUK

MICHELE BONANOMI

BRUNO SILVESTRINI

C. YAN CHENG

REN-SHAN GE^*,

From the ^* Institute of Molecular Toxicology and Pharmacology, School of Pharmacy, and the Institute of Molecular Pathology, 1st Affiliated Hospital, Wenzhou Medical College, Wenzhou, China; Population Council and Rockefeller University, New York, NY; and Bioprogress Pharmaceuticals S.p.A., Rome, Italy.

Correspondence to: Ren-Shan Ge or C. Yan Cheng, Population Council, 1230 York Avenue, New York, NY 10065 (e-mail: rge{at}popcbr.rockefeller.edu or Y-Cheng{at}popcbr.rockefeller.edu).

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 Sertoligerm cell interface. This, in turn, leads to germ cell loss from the seminiferous epithelium, and transient infertility. Adjudin's efficacyin inhibiting spermatogenesis, the recovery of spermatogenesis after cessation of the drug, and side effects were examined in adult male Japanese rabbits. The pharmacokinetics 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. At 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 also was monitored. Blood was withdrawn after first administration to measure plasma concentrations of adjudin by high-performance liquid chromatography. Four weeks after intravenous treatment, examination of testis sections showed rapid exfoliation of elongated/elongating spermatids and the presence of large multinucleated cells; more than 95% of germ cells were absent from the seminiferous epithelium. Intravenous treatment showed a more severe disturbance of spermatogenesis compared with gavage treatment, which was correlated with bioavailability of the drug. The areas under the curve for intravenous injection and 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: Male contraception, testis, Sertoli-germ cell adhesion

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