Intestinal absorption mechanism of amphoteric β-lactam antibiotics II: Michaelis—menten kinetics of cyclacillin absorption and its pharmacokinetic analysis in rats

doi:10.1002/jps.2600700715

Journal of Pharmaceutical Sciences

Volume 70, Issue 7, July 1981, Pages 772-777

https://doi.org/10.1002/jps.2600700715 Get rights and content

Abstract

The absorption of cyclacillin at pH 7.0 by the rat small intestine was investigated using in situ perfusion. At the lowest dose of 95 μ/ml, the antibiotic disappearance was rapid and followed first-order kinetics, with the disappearance being 85% at 100 min. At the intermediate concentrations of 770 and 1200 μ/ml, the disappearance after 100 min was 69 and 54%, respectively, and semilogarithmic plots clearly showed convex curvatures. At the highest concentration of 30 mg/ml, cyclacillin disappeared slowly from the perfusate, in an apparent first-order fashion. The disappearance was 26% after 100 min of perfusion and was similar in extent at 5.2 mg/ml. This concentration-time profile was satisfactorily fitted to the simultaneous Michaelis-Menten and first-order kinetic equations. The area under the blood concentration versus time curve (AUC) after a single intraduodenal dose of cyclacillin was almost consistent with the AUC after the equivalent intravenous dose (10 mg/kg). Additional evidence from a pharmacokinetic analysis of steady-state blood concentrations after constant infusion of cyclacillin through the portal vein and the small intestinal lumen indicated that cyclacillin absorption by the rat intestinal tissue at relatively low concentrations (<1 mg/ml) followed solely Michaelis-Menten kinetics. Cyclacillin may be transported by certain types of carrier-mediated mechanisms.

References (21)

De YoungJ.L. et al.
J. Pharm. Sci.
(1978)
TsujiA. et al.
J. Pharm. Sci.
(1979)
GibaldiM. et al.
J. Pharm. Sci.
(1969)
TsujiA. et al.
J. Pharm. Pharmacol.
(1977)
TsujiA. et al.
J. Pharm. Pharmacol.
(1978)
TsujiA. et al.
J. Pharm. Pharmacol.
(1979)
TsujiA. et al.
J. Pharm Sci.
(1981)
QuayJ.F. et al.
Physiologist
(1970)
QuayJ.F.
Physiologist
(1972)
MiyazakiK. et al.
Chem Pharm Bull
(1977)

There are more references available in the full text version of this article.

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Journal of Pharmaceutical Sciences

Research ArticlesIntestinal absorption mechanism of amphoteric β-lactam antibiotics II: Michaelis—menten kinetics of cyclacillin absorption and its pharmacokinetic analysis in rats

Abstract

J. Pharm. Sci.

J. Pharm. Sci.

J. Pharm. Sci.

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Physiologist

Physiologist

Chem Pharm Bull

Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal

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Molecular determinants of recognition for the intestinal peptide carrier

The intestinal peptide carrier: A potential transport system for small peptide derived drugs

Characterization of the oral absorption of some β‐lactams: Effect of the α‐amino side chain group

Characterization of the oral absorption of several aminopenicillins: Determination of intrinsic membrane absorption parameters in the rat intestine in situ

Research Articles
Intestinal absorption mechanism of amphoteric β-lactam antibiotics II: Michaelis—menten kinetics of cyclacillin absorption and its pharmacokinetic analysis in rats