Pharmacokinetic and pharmacodynamic studies of the effect of ketoconazole on reproductive function in male rats |
| |
Authors: | J. M. WANG X. L. WU W. YOU L. X. LING J. WU G. Y. ZHANG |
| |
Affiliation: | Department of Pharmacology, Nanjing Institute of Materia Medica, People's Republic of China. |
| |
Abstract: | A single oral dose (300 mg kg-1) of ketoconazole induced reversible immobilization of rat epididymal spermatozoa at 8-24 h after dosing. This occurred when the drug concentrations in cauda epididymal fluid and seminal plasma were at their peak (18.0 +/- 7.3 and 13.5 +/- 3.0 micrograms ml-1, respectively), and which was preceded by a peak plasma concentration (Cmax) of 64.82 +/- 2.47 micrograms ml-1 at 5.15 +/- 0.68 h (Tmax). In contrast, rete testis fluid collected from the same animals contained only minute amounts of ketoconazole (0.47 +/- 0.34 micrograms ml-1). Plasma testosterone concentration showed a sharp decline within 4 h of dosing, followed by a recovery from suppression, even after administration of a low dose (100 mg kg-1) which did not affect sperm motility. These findings suggest that ketoconazole gains access to the post-testicular sex organs and affects the mature spermatozoa therein much more readily than it affects testicular spermatogenesis. Synthesis and screening of compounds with a related molecular structure but which exhibit more pronounced spermicidal and less pronounced anti-androgenic effects are thus suggested in the hope that rapidly acting and reversible male contraceptives might be identified and developed. |
| |
Keywords: | cauda epididymal fluid HPLC ketoconazole pharmacokinetics plasma testosterone concentration rete testis fluid seminal plasma sperm motility |
|
|