Pharmacokinetic interaction between cefdinir and two angiotensin-converting enzyme inhibitors in rats

Abstract

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.

Analysis of the Pharmacokinetic Interaction between Cephalexin and Quinapril by a Nonlinear Mixed-Effect Model

“…However, there is a second putative site of interaction between ACE inhibitors and ␤-lactams. Indeed, ␤-lactams (2, 7) and ACE inhibitors (14) have been shown to be excreted by the renal anionic transport system, and concomitant administration of both drugs sometimes results in a pronounced inhibition of ␤-lactam elimination (10). The second goal of our study was therefore to characterize cephalexin elimination kinetics when cephalexin was associated with quinapril.…”

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“…Quinapril's high affinity for the organic anion transporter suggests that potential drug-drug interactions may readily occur with other organic anions. This belief is supported by an in vivo rat study (35) in which quinapril substantially increased cefdinir's area under the curve and half-life, but decreased its clearance as a result of competition at the tubular anion transporter. Captopril had similar effects on cefdinir pharmacokinetics, but of lesser magnitude.…”

Lack of Interaction Between the Peptidomimetic Substrates Captopril and Cephradine

“…14 Jacolot and colleagues demonstrated that intra-intestinal administration of captopril in rats causes a marked increase in the half-life of the cephalosporin cefdinir. 36 In a subsequent experiment, the same group administered cephalexin (a cephalosporin) and quinapril (an ACE inhibitor) to rats, using different routes of administration (ie, oral and parenteral administration). They found that while parenteral administration of quinapril did not alter the disposition of either orally or parenterally administered cephalexin, the co-administration of oral cephalexin and oral quinapril resulted in a 30% decrease in cephalexin oral clearance and a 30% increase in cephalexin AUC.…”

“…Similarly, in vitro investigations have described the saturable transport of ACE inhibitors by the renal peptide transporters hPEPT1 and hPEPT2 14 . Jacolot and colleagues demonstrated that intra‐intestinal administration of captopril in rats causes a marked increase in the half‐life of the cephalosporin cefdinir 36 . In a subsequent experiment, the same group administered cephalexin (a cephalosporin) and quinapril (an ACE inhibitor) to rats, using different routes of administration (ie, oral and parenteral administration).…”