Characterization of the Oral Absorption of β-Lactam Antibiotics. I. Cephalosporins

Determination of Intrinsic Membrane Absorption Parameters in the Rat Intestine In Situ

Patrick Sinko, Gordon L. Amidon

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

The oral absorption of five cephalosporin antibiotics, cefaclor, cefadroxil, cefatrizine, cephalexin, and cephradine, has been studied using a single-pass intestinal perfusion technique in rats. Intrinsic membrane absorption parameters, “unbiased” by the presence of an aqueous permeability (diffusion or stagnant layer), have been calculated utilizing a boundary layer mathematical model. The resultant intrinsic membrane absorption parameters are consistent with a significant carrier-mediated, Michaelis-Menten-type kinetic mechanism and a small passive component in the jejunum. Cefaclor colon permeability is low and does not exhibit concentration dependent behavior. The measured carrier parameters (±SD) for the jejunal perfusions are as follows: cefaclor, Jmax * = 21.3 (±4.0), Km = 16.1 (±3.6), Pm * = 0, and Pc *= 1.32 (±0.07); cefadroxil, Jmax * = 8.4 (±0.8), Km = 5.9 (±0.8), Pm * = 0, and Pc * = 1.43 (±0.10); cephalexin, Jmax * = 9.1 (±1.2), Km = 7.2 (±1.2), Pm * = 0, and Pc * = 1.30 (±0.10); cefatrizine, Jmax * = 0.73 (±0.19), Km = 0.58 (±0.17), Pm * = 0.17 (±0.03), and Pc * = 1.25 (±0.10); and cephradine, Jmax * = 1.57 (±0.84), Km = 1.48 (±0.75), Pm * = 0.25 (±0.07), and Pc * = 1.06 (±0.08). The colon absorption parameter for cefaclor is Pm * = 0.36 (±0.06, where Jmax * (m M) is the maximal flux, Km (m M) is the Michaelis constant, Pm * is the passive membrane permeability, and Pc*is the carrier permeability. Aminocephalosporin perfusion results indicate that jejunal absorption in the rat occurs by a nonpassive process, with some of the compounds possessing a small but statistically significant passive component, while the colon permeability is low and follows a simple passive absorption mechanism.

Original languageEnglish (US)
Pages (from-to)645-650
Number of pages6
JournalPharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists
Volume5
Issue number10
DOIs
StatePublished - Jan 1 1988

Fingerprint

Cefaclor
Lactams
Cephalosporins
Intestines
Rats
Cefatrizine
Cefadroxil
Cephradine
Permeability
Anti-Bacterial Agents
Membranes
Cephalexin
Colon
Perfusion
Boundary layers
Jejunum
Mathematical models
Fluxes
Kinetics
Theoretical Models

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)
  • Molecular Medicine
  • Biotechnology
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Keywords

  • colon
  • concentration dependent absorption
  • intrinsic permeability
  • jejunum
  • nonpassive absorption
  • unstirred layer

Cite this

@article{02a171f774784d1898797e9d0d3aae11,
title = "Characterization of the Oral Absorption of β-Lactam Antibiotics. I. Cephalosporins: Determination of Intrinsic Membrane Absorption Parameters in the Rat Intestine In Situ",
abstract = "The oral absorption of five cephalosporin antibiotics, cefaclor, cefadroxil, cefatrizine, cephalexin, and cephradine, has been studied using a single-pass intestinal perfusion technique in rats. Intrinsic membrane absorption parameters, “unbiased” by the presence of an aqueous permeability (diffusion or stagnant layer), have been calculated utilizing a boundary layer mathematical model. The resultant intrinsic membrane absorption parameters are consistent with a significant carrier-mediated, Michaelis-Menten-type kinetic mechanism and a small passive component in the jejunum. Cefaclor colon permeability is low and does not exhibit concentration dependent behavior. The measured carrier parameters (±SD) for the jejunal perfusions are as follows: cefaclor, Jmax * = 21.3 (±4.0), Km = 16.1 (±3.6), Pm * = 0, and Pc *= 1.32 (±0.07); cefadroxil, Jmax * = 8.4 (±0.8), Km = 5.9 (±0.8), Pm * = 0, and Pc * = 1.43 (±0.10); cephalexin, Jmax * = 9.1 (±1.2), Km = 7.2 (±1.2), Pm * = 0, and Pc * = 1.30 (±0.10); cefatrizine, Jmax * = 0.73 (±0.19), Km = 0.58 (±0.17), Pm * = 0.17 (±0.03), and Pc * = 1.25 (±0.10); and cephradine, Jmax * = 1.57 (±0.84), Km = 1.48 (±0.75), Pm * = 0.25 (±0.07), and Pc * = 1.06 (±0.08). The colon absorption parameter for cefaclor is Pm * = 0.36 (±0.06, where Jmax * (m M) is the maximal flux, Km (m M) is the Michaelis constant, Pm * is the passive membrane permeability, and Pc*is the carrier permeability. Aminocephalosporin perfusion results indicate that jejunal absorption in the rat occurs by a nonpassive process, with some of the compounds possessing a small but statistically significant passive component, while the colon permeability is low and follows a simple passive absorption mechanism.",
keywords = "colon, concentration dependent absorption, intrinsic permeability, jejunum, nonpassive absorption, unstirred layer",
author = "Patrick Sinko and Amidon, {Gordon L.}",
year = "1988",
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TY - JOUR

T1 - Characterization of the Oral Absorption of β-Lactam Antibiotics. I. Cephalosporins

T2 - Determination of Intrinsic Membrane Absorption Parameters in the Rat Intestine In Situ

AU - Sinko, Patrick

AU - Amidon, Gordon L.

PY - 1988/1/1

Y1 - 1988/1/1

N2 - The oral absorption of five cephalosporin antibiotics, cefaclor, cefadroxil, cefatrizine, cephalexin, and cephradine, has been studied using a single-pass intestinal perfusion technique in rats. Intrinsic membrane absorption parameters, “unbiased” by the presence of an aqueous permeability (diffusion or stagnant layer), have been calculated utilizing a boundary layer mathematical model. The resultant intrinsic membrane absorption parameters are consistent with a significant carrier-mediated, Michaelis-Menten-type kinetic mechanism and a small passive component in the jejunum. Cefaclor colon permeability is low and does not exhibit concentration dependent behavior. The measured carrier parameters (±SD) for the jejunal perfusions are as follows: cefaclor, Jmax * = 21.3 (±4.0), Km = 16.1 (±3.6), Pm * = 0, and Pc *= 1.32 (±0.07); cefadroxil, Jmax * = 8.4 (±0.8), Km = 5.9 (±0.8), Pm * = 0, and Pc * = 1.43 (±0.10); cephalexin, Jmax * = 9.1 (±1.2), Km = 7.2 (±1.2), Pm * = 0, and Pc * = 1.30 (±0.10); cefatrizine, Jmax * = 0.73 (±0.19), Km = 0.58 (±0.17), Pm * = 0.17 (±0.03), and Pc * = 1.25 (±0.10); and cephradine, Jmax * = 1.57 (±0.84), Km = 1.48 (±0.75), Pm * = 0.25 (±0.07), and Pc * = 1.06 (±0.08). The colon absorption parameter for cefaclor is Pm * = 0.36 (±0.06, where Jmax * (m M) is the maximal flux, Km (m M) is the Michaelis constant, Pm * is the passive membrane permeability, and Pc*is the carrier permeability. Aminocephalosporin perfusion results indicate that jejunal absorption in the rat occurs by a nonpassive process, with some of the compounds possessing a small but statistically significant passive component, while the colon permeability is low and follows a simple passive absorption mechanism.

AB - The oral absorption of five cephalosporin antibiotics, cefaclor, cefadroxil, cefatrizine, cephalexin, and cephradine, has been studied using a single-pass intestinal perfusion technique in rats. Intrinsic membrane absorption parameters, “unbiased” by the presence of an aqueous permeability (diffusion or stagnant layer), have been calculated utilizing a boundary layer mathematical model. The resultant intrinsic membrane absorption parameters are consistent with a significant carrier-mediated, Michaelis-Menten-type kinetic mechanism and a small passive component in the jejunum. Cefaclor colon permeability is low and does not exhibit concentration dependent behavior. The measured carrier parameters (±SD) for the jejunal perfusions are as follows: cefaclor, Jmax * = 21.3 (±4.0), Km = 16.1 (±3.6), Pm * = 0, and Pc *= 1.32 (±0.07); cefadroxil, Jmax * = 8.4 (±0.8), Km = 5.9 (±0.8), Pm * = 0, and Pc * = 1.43 (±0.10); cephalexin, Jmax * = 9.1 (±1.2), Km = 7.2 (±1.2), Pm * = 0, and Pc * = 1.30 (±0.10); cefatrizine, Jmax * = 0.73 (±0.19), Km = 0.58 (±0.17), Pm * = 0.17 (±0.03), and Pc * = 1.25 (±0.10); and cephradine, Jmax * = 1.57 (±0.84), Km = 1.48 (±0.75), Pm * = 0.25 (±0.07), and Pc * = 1.06 (±0.08). The colon absorption parameter for cefaclor is Pm * = 0.36 (±0.06, where Jmax * (m M) is the maximal flux, Km (m M) is the Michaelis constant, Pm * is the passive membrane permeability, and Pc*is the carrier permeability. Aminocephalosporin perfusion results indicate that jejunal absorption in the rat occurs by a nonpassive process, with some of the compounds possessing a small but statistically significant passive component, while the colon permeability is low and follows a simple passive absorption mechanism.

KW - colon

KW - concentration dependent absorption

KW - intrinsic permeability

KW - jejunum

KW - nonpassive absorption

KW - unstirred layer

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U2 - https://doi.org/10.1023/A:1015974920682

DO - https://doi.org/10.1023/A:1015974920682

M3 - Article

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EP - 650

JO - Pharmaceutical Research

JF - Pharmaceutical Research

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