Effect of concurrently coadministered drugs on the pharmacokinetic/pharmacodynamic profile of centchroman, a nonsteroidal oral contraceptive, in rats.
BACKGROUND
Centchroman (international nonproprietary name: ormeloxifene) is a nonsteroidal selective estrogen receptor modulator, oral contraceptive, anticancer and antiosteoporotic agent that is intended for long-term use by women. In view of the vast clinical applications and interactions of steroidal oral contraceptives with commonly used therapeutic agents, the interaction potential of certain concomitantly administered therapeutic agents was investigated in terms of postcoital contraceptive efficacy (pharmacological) and the pharmacokinetic profile of centchroman in female Sprague-Dawley rats. The coadministered drugs used in the study were ciprofloxacin, cefixime, amoxicillin, metronidazole, amlodipine, atenolol, theophylline, metformin, pioglitazone and glibenclamide.


METHODS
The pharmacological activity of centchroman was evaluated in sperm-positive female rats at 1.5 mg/kg, with or without coadministered drugs. Rats were sacrificed on Day 10 postcoitus, and autopsy was performed to check for the presence or absence of implantations. The estrogenic and antiestrogenic activities of centchroman were evaluated in immature ovariectomized rats. Pharmacokinetic interaction was studied in normal female rats with or without coadministered drugs. Serum samples were taken over 120 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of centchroman. Pharmacokinetic parameters were estimated using noncompartmental analysis, and the results were compared.


RESULTS
In pharmacological interaction studies, centchroman alone showed a 100% success rate when given alone or in the presence of coadministered drugs. The only exception was amoxicillin coadministration, with 66% rats in the group showing resorbed implantations. Further investigation with amoxicillin in ovariectomized immature rats indicates no alteration in the estrogenic and antiestrogenic profiles of centchroman. In pharmacokinetic interaction studies, most of the therapeutic agents affected the rate and extent of absorption of centchroman. In other pharmacokinetic parameters, clearance (CL) remained unchanged; however, there was decrease in bioavailability (F) and volume of distribution (V(d)) in some situations.


CONCLUSIONS
The results indicate that there is no direct link between the altered pharmacokinetics of centchroman and the failure of pharmacological effect. The pharmacological interaction with amoxicillin could not be explained on the basis of alteration in the estrogenic and antiestrogenic activities of centchroman, indicating that different mechanisms are involved. The findings, however, suggest that amoxicillin coadministration may result in pharmacological interaction with centchroman and that caution should be taken in clinical practice.
Kumar
Vipul
V
Pharmacokinetics and Metabolism Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India.
Lal
Jawahar
J
Singh
Man Mohan
MM
Gupta
Ram Chandra
RC
D000658:Amoxicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002486:Centchroman / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003276:Contraceptives, Oral / Q000008:administration & dosage; D003281:Contraceptives, Postcoital; D004347:Drug Interactions; D010064:Embryo Implantation / Q000187:drug effects; D004965:Estrogen Antagonists / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D008297:Male; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley
D000900:Anti-Bacterial Agents; D003276:Contraceptives, Oral; D003281:Contraceptives, Postcoital; D004965:Estrogen Antagonists; D002486:Centchroman; D004997:Ethinyl Estradiol; D000658:Amoxicillin