Kinetics of Michaelis-Menten absorption of amino-penicillins in rats

Tsuji, Akira; Nakashima, Emi; Kagami, Izumi; Asano, Tetsuo; Nakashima, Ryoko; Yamana, Tsukinaka

doi:10.1111/j.2042-7158.1978.tb13304.x

Journal of Pharmacy and Pharmacology

1978

DOI: 10.1111/j.2042-7158.1978.tb13304.x

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Kinetics of Michaelis-Menten absorption of amino-penicillins in rats

Akira Tsuji

Emi Nakashima

Izumi Kagami

et al.

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Cited by 16 publications

(1 citation statement)

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“…The p-lactam aminopenicillins, such as ampicillin, amoxicillin, and cyclacillin, are relatively well absorbed from the small intestine. Since they are ionized at the physiological pH and have low partition coefficients, it has been suggested that the mechanism of intestinal absorption of the aminopenicillins may be a saturable absorption process in the rat (Dixon and Mizen, 1977;Tsuji et al, 1977Tsuji et al, , 1978Tsuji et al, , 1981aKimura et al, 1978Kimura et al, , 1983Shindo et al, 1978;Iseki et al, 1984;Nakashima et al, 1984). However, there are conflicting reports in the literature on the absorption mechanism.…”

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confidence: 99%

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

Oh¹,

Sinko²,

Amidon³

1992

International Journal of Pharmaceutics

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The absorption mechanism of several penicillins was characterized using in situ single-pass intestinal perfusion in the rat. The intrinsic membrane parameters were determined using a modified boundary layer model (fitted value +/- S.E.): Jmax* = 11.78 +/- 1.88 mM, Km = 15.80 +/- 2.92 mM, Pm* = 0, Pc* = 0.75 +/- 0.04 for ampicillin; Jmax* = 0.044 +/- 0.018 mM, Km = 0.058 +/- 0.026 mM, Pm* = 0.558 +/- 0.051, Pc* = 0.757 +/- 0.088 for amoxicillin; and Jmax* = 16.30 +/- 3.40 mM, Km = 14.00 +/- 3.30 mM, Pm* = 0, Pc* = 1.14 +/- 0.05 for cyclacillin. All of the aminopenicillins studied demonstrated saturable absorption kinetics as indicated by their concentration-dependent wall permeabilities. Inhibition studies were performed to confirm the existence of a nonpassive absorption mechanism. The intrinsic wall permeability (Pw*) of 0.01 mM ampicillin was significantly lowered by 1 mM amoxicillin and the Pw* of 0.01 mM amoxicillin was reduced by 2 mM cephradine consistent with competitive inhibition.

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mentioning

confidence: 99%

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

Oh¹,

Sinko²,

Amidon³

1992

International Journal of Pharmaceutics

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Nonlinearities in amoxycillin pharmacokinetics II. Absorption studies in the rat

Torres‐Molina

Peris-Ribera

García-Carbonell

et al. 1992

Biopharm & Drug Disp

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Most factors influencing amoxycillin oral absorption are, even today, unknown. Since many dosage schedules have been shown to lead to incomplete absorption, it would be desirable to find a suitable animal model where these factors could be studied in depth. In this paper, it is shown that, in the rat, plasma level curves obtained after oral doses of 7 and 28 mg kg-1 are poorly fitted using first-order absorption kinetics and that the best fit is obtained through the use of an input equation combining zero and first-order kinetics. In contrast, plasma level curves found after intraduodenal administration of amoxycillin solutions (7 mg kg-1) are well fitted by first-order input kinetics. It would seem that precipitation of some dose fraction of the orally administered antibiotic may occur in proximal gastrointestinal areas; this plays an important role in absorption profiles and prevents any possible saturation phenomena associated with active intestinal transport of the antibiotic. A comparative study of available human oral data revealed close similarities with those found in rats. As a result, the plasma level curve fitting was greatly improved by the use of the input function described here for the rat. Although oral bioavailability (as assessed from urinary excretion data) is lower in this latter species, the use of suitable correction factors led to superimposable plasma level curves in the two species, as occurred in previously reported disposition studies.

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Dose‐dependent pharmacokinetics: Experimental observations and theoretical considerations

Lin

1994

Biopharm & Drug Disp

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Clinically, absorption and elimination of most drugs follow linear kinetics, and pharmacokinetic parameters describing absorption and elimination of a drug do not change over the therapeutic dose range. However, dose-dependent pharmacokinetics have been reported more frequently in preclinical studies, particularly in toxicity studies, where high doses are often employed. This review highlights the major types of dose-dependent pharmacokinetics with unique examples.Before setting out on a pivotal subchronic and chronic toxicity study of a new drug, a pilot study is often performed to establish a dose range in which a reasonable relationship between plasma AUC and dosage exists to ensure sufficient exposure of animals to the drug. Theoretical bases and possible causes of dose-AUC disproportionality are discussed.Factors affecting the distribution and elimination of drugs and causes of dose-dependent tissue distribution and elimination are also discussed. Often, the non-linear kinetics complicate the design of dosage regimens and prediction of efficacy and toxicity. Thus, an understanding of the influence of dose on the pharmacokinetics is important in the evaluation of the efficacy and toxicity of new drugs.

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Kinetics of Michaelis-Menten absorption of amino-penicillins in rats

Cited by 16 publications

References 4 publications

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

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

Nonlinearities in amoxycillin pharmacokinetics II. Absorption studies in the rat

Dose‐dependent pharmacokinetics: Experimental observations and theoretical considerations

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