title: Pharmacokinetic and pharmacodynamic studies of the effect of ketoconazole on reproductive function in male rats.
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.
authors.affiliation: Department of Pharmacology, Nanjing Institute of Materia Medica, People's Republic of China.
authors.forename: J M
authors.initials: JM
authors.lastname: Wang
authors.forename: X L
authors.initials: XL
authors.lastname: Wu
authors.forename: W
authors.initials: W
authors.lastname: You
authors.forename: L X
authors.initials: LX
authors.lastname: Ling
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: G Y
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000728:Androgens / Q000096:biosynthesis; D000818:Animals; D004822:Epididymis / Q000166:cytology; D005837:Genitalia, Male / Q000378:metabolism*; D007654:Ketoconazole / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013081:Sperm Motility / Q000187:drug effects; D013739:Testosterone / Q000097:blood
chemical_list: D000728:Androgens; D013739:Testosterone; D007654:Ketoconazole