Adjudin targeting rabbit germ cell adhesion as a male contraceptive: A pharmacokinetics study
Hu,Guo-Xin; Hu,Lu-Feng; Yang,Dai-Zheng; Li,Jun-Wei; Chen,Guo-Rong; Chen,Bing-Bing; Mruk,Dolores D.; Bonanomi,Michele; Silvestrini,Bruno; Cheng,Chuen-yan; Ge,Renshan
Journal of Andrology 30(1): 87-93
Publication date: 2009
Adjudin (1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide;formerly called AF-2364) has been shown to inhibit spermatogenesisby disrupting anchoring junctions at the Sertoligerm cell interface.This, in turn, leads to germ cell loss from the seminiferousepithelium, and transient infertility. Adjudin's efficacyininhibiting spermatogenesis, the recovery of spermatogenesisafter cessation of the drug, and side effects were examinedin adult male Japanese rabbits. The pharmacokinetics profilesof adjudin in rabbits after oral administration and after intravenousinjection were compared. Rabbits received 25 mg/kg adjudinonce weekly for 4 consecutive weeks either by intravenous injectionor by gavage. Vehicle-treated rabbits were used as controls.At 1, 2, 3, 4, and 8 weeks after treatment, testes were removedfor microscopic examination to assess the status of spermatogenesis.Four weeks after intravenous cessation of adjudin, the recoveryof spermatogenesis also was monitored. Blood was withdrawnafter first administration to measure plasma concentrationsof adjudin by high-performance liquid chromatography. Fourweeks after intravenous treatment, examination of testis sectionsshowed rapid exfoliation of elongated/elongating spermatidsand 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 spermatogenesiscompared with gavage treatment, which was correlated with bioavailabilityof the drug. The areas under the curve for intravenous injectionand gavage were 20.11 ± 1.90 and 2.23 ± 0.45mg·h·L, respectively. These results illustratethe potential of adjudin as a male contraceptive, and the efficacyis associated with the bioavailability of the drug.