Pharmacokinetic interaction between cefdinir and two angiotensin-converting enzyme inhibitors in rats.
The pharmacokinetic interaction between cefdinir and an angiotensin-converting enzyme inhibitor (captopril or quinapril) was investigated in rats. The linearity of cefdinir pharmacokinetics was demonstrated in three groups of rats receiving 10, 20, or 40 mg of cefdinir per kg of body weight intravenously. Then, three other groups of rats were established as follows: group 1 (n = 5) received cefdinir (10 mg/kg) intravenously, and 12 blood samples per rat were drawn between 0 and 8 h after injection of the dose; group 2 (n = 5) was treated in the same way as group 1, but captopril (0.8 mg/kg) was coadministered by intraintestinal injection into all animals; group 3 (n = 6) was treated in the same way as group 2, but quinapril (0.8 mg/kg) replaced captopril. Plasma cefdinir concentrations were measured by liquid chromatography, and the data were analyzed by a noncompartmental method. Finally, three groups of four or five rats each were set up as described above, but the cefdinir dose was 20 mg/kg and the animals were sacrificed 1 h after drug injection to collect blood to determine the unbound cefdinir fraction (fu) by ultrafiltration. The angiotensin-converting enzyme inhibitors increased the mean cefdinir area under the concentration-time curve up to 8 h by a factor of 1.8 (captopril; P < 0.05) and a factor of 3.5 (quinapril; P < 0.05). With captopril, mean cefdinir clearance was decreased by a factor of 2, and the volume of distribution increased by the same factor, while the fu increased from 15.4% +/- 3.0% (cefdinir alone) to 22.8% +/- 10.9% (cefdinir plus captopril). Captopril increased the cefdinir half-life from 0.62 +/- 0.17 to 2.92 +/- 0.95 h. With quinapril, the interaction was so strong that no elimination phase was detectable in four of the six rats, and therefore, no pharmacokinetic parameter values other than the cefdinir fu could be calculated; the cefdinir fu increased to 25.1% +/- 11.1%. It is concluded that captopril and quinapril (and/or their metabolites) have a major impact on the disposition of cefdinir in rats, probably by competition at the plasma protein-binding level and at the tubular anionic carrier level. This latter mechanism should also be relevant in humans.
Jacolot
A
A
Département de Pharmacotoxicologie, Hôpital Avicenne, Bobigny, France.
Tod
M
M
Petitjean
O
O
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology; D000077525:Cefdinir; D002511:Cephalosporins / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006207:Half-Life; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D000077583:Quinapril; D051381:Rats; D017208:Rats, Wistar; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D002511:Cephalosporins; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D002216:Captopril; D000077525:Cefdinir; D000077583:Quinapril