Interaction with anti-implantation and estrogen antagonistic activities of dl-ormeloxifene, a selective estrogen receptor modulator, by tetracycline in female Sprague-Dawley rats

Among the 10 commonly used therapeutic agents investigated, concurrent oral administration of tetracycline (140 mg/kg) twice daily on Days 1-5 post-coitum (pc) interfered with the post-coital anti-implantation activity and almost completely abolished estrogen antagonistic activity of the single anti-implantation (1.5 mg/kg, orally) dose of dl-ormeloxifene administered on Day I pc, resulting in the occurrence of resorbed implantations in 50% of the females, However, no such interaction was evident when tetracycline was administered intramuscularly or when ormeloxifene was administered at twice its anti-implantation dose. There was no effect of ormeloxifene and/or tetracycline treatment on serum estradiol and progesterone levels, and all animals presented apparently normal corpora lutea. Ormeloxifene administered per se inhibited aminopyrine-N-demethylase (AD), glucose-6-phosphate dehydrogenase (G-6-PDH) and glutathione-S-transferase (GST) in the liver on the day of maximal endometrial receptivity, which was prevented by tetracycline co-administration. Aniline hydroxylase and AD were not detected in small intestine or uterus in vehicle control or any of the treatment groups. There was, however, no effect of ormeloxifene plus tetracycline treatment on serum total alkaline phosphatase activity. Findings suggest that interference with anti-implantation action of ormeloxifene by tetracycline might be due primarily to the almost complete abolition of its estrogen antagonistic activity at the uterine level, effected by decreased bioavailability of ormeloxifene and/or its active metabolite(s) by altered enterohepatic recirculation because of the effect on gut microflora. This might alternatively be related to an increased rate of its metabolism and elimination from the system via prevention of ormeloxifene-induced inhibition of hepatic AD, G-6-PDH, and GST, which, by effecting a decreased rate of metabolism, might be responsible for prolonged (similar to 120 h) duration of estrogen antagonistic/anti-implantation action of ormeloxifene in this species. (C) 2001 Elsevier Science Inc, All rights reserved.