Increased intestinal absorption of cefixime by nifedipine in the rat intestinal perfusion model: evidence for a neural regulation.
In healthy volunteers, the simultaneous administration of nifedipine and cefixime has been shown to increase the oral absorption of the antibiotic. To investigate the pharmacological basis of this interaction, we used an in situ intestinal perfusion technique in the rat. pH 5.5 yielded optimum cefixime absorption, which was greater in segments from the duodenojejunum than in those from the jejunoileum. Cefixime absorption was similar when perfused at 0.5 and 1.0 mg/ml, suggesting transport saturation at the lower concentration. Cefixime arterial and portal blood concentrations after an intestinal perfusion of 0.5 mg/ml cefixime were significantly increased by a previous 15-min intestinal perfusion of 0.05 mg/ml nifedipine. Nifedipine did not significantly alter intestinal blood flow. At the end of the cefixime perfusion, intestinal blood flow was higher in the nifedipine group than in the control group (0.44 +/- 0.12 vs. 0.26 +/- 0.09 ml.min-1.g of intestine wt-1, respectively), although the difference did not reach statistical significance. The absorption kinetics of salicylic acid, which is strictly absorbed by passive diffusion, were unaffected by nifedipine. After 15 and 50 min of recirculation, residual salicylate levels fell from 85.1 +/- 5.6% to 57.1 +/- 2.8% with nifedipine compared with 87.4 +/- 1.4% to 52.8 +/- 1.6% without nifedipine. Thus, the improvement in cefixime absorption by nifedipine was not secondary to increased local blood flows or to induced passive diffusion mechanisms. Nifedipine did not affect intestinal motility. The action of nifedipine appears to indirect, involving a neural regulation, because any increase in cefixime absorption was prevented by tetrodotoxin and hexamethonium administration.
Harcouët
L
L
Départment de Pharmacie Clinique, Faculté de Pharmacie, Chatenay-Malabry, France.
Lebrec
D
D
Rozé
C
C
Carbon
C
C
Farinotti
R
R
D000818:Animals; D020682:Cefixime; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004357:Drug Synergism; D017615:Enteric Nervous System / Q000187:drug effects* / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D008954:Models, Biological; D009543:Nifedipine / Q000494:pharmacology*; D019894:Peptide YY; D010455:Peptides / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000493:pharmacokinetics; D020156:Salicylic Acid
D010455:Peptides; D012459:Salicylates; D019894:Peptide YY; D020682:Cefixime; D009543:Nifedipine; D002439:Cefotaxime; D020156:Salicylic Acid