Journal of Pharmacokinetics and Biopharmaceutics

, Volume 15, Issue 5, pp 529–544

The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon

  • Rebecca L. Oberle
  • Gordon L. Amidon
Pharmacometrics

DOI: 10.1007/BF01061761

Cite this article as:
Oberle, R.L. & Amidon, G.L. Journal of Pharmacokinetics and Biopharmaceutics (1987) 15: 529. doi:10.1007/BF01061761

Abstract

A physiological flow model is presented to account for plasma level double peaks based on cyclical gastric emptying and intestinal motility in the fasted state. Central to the model is the assumption that gastric emptying and intestinal transit rates will vary directly with the strength of the contractile activity characteristic of the fasted state motility cycle. Simulated curves clearly indicate that variable gastric emptying rates can result in variable absorption rates from the gastrointestinal tract and double peaks in the plasma level curves of cimetidine. Vital to the occurrence of double peaks are (i) dosing time relative to phasic activity, (ii) variability in flow out of the stomach, and (iii) a small emptying rate constant Qs/Vs, for a period of time within the first hour after administration. Variability in intestinal flow rates alone does not cause a double peak in the plasma level curve. Results of the simulations, as well as experimental results, can be categorized according to the shapes of the plasma level curves into four types: type A, Cpmax(1) <Cpmax(2); type B, single peak; type C, Cpmax(1)>Cpmax(2); type D, Cpmax(1)=Cpmax(2). Assuming that the experimental results were obtained from fasted subjects, with the time of dose administration being a random variable, the frequency of the experimental curves having shape A, B, C, or D correlates extremely well with theoretical predictions. It is concluded that variable gastric emptying rates due to the motility cycle can account for plasma level double peaks. Furthermore, variable gastric emptying rates combined with the short plasma elimination half-life and poor gastric absorption of cimetidine can be the cause of the frequently observed plasma level double peaks.

Key words

cimetidine oral absorption double peaks gastric emptying fasted motility 

Notation

As

Amount of drug in the stomach

Ad

Amount of drug in the duodenum

Aj

Amount of drug in the jejunum

Ai

Amount of drug in the ileum

Ap

Amount of drug in the plasma

At

Amount of drug in the peripheral compartment

Qs

Flow rate exiting the stomach

Qd

Flow rate exiting the duodenum

Qj

Flow rate exiting the jejunum

Qi

Flow rate exiting the ileum

Vs

Volume of stomach contents

Vd

Volume of duodenal contents

Vj

Volume of jejunal contents

Vi

Volume of ileal contents

Vp

Volume of distribution

Vso

Initial volume of stomach contents

Kas

Absorption rate constant of cimetidine from the stomach

Kad

Absorption rate constant of cimetidine from the duodenum

Kaj

Absorption rate constant of cimetidine from the jejunum

Kai

Absorption rate constant of cimetidine from the ileum

K12

Distribution rate constant of cimetidine from plasma to tissue

K21

Distribution rate constant of cimetidine from tissue to plasma

K10

Elimination rate constant of cimetidine from the plasma

I

Input of drug into the plasma from the gastrointestinal tract

DER

Emptying rate of the drug from the stomach into the duodenum

Cpmax(1)

First maximum drug concentration in the plasma

Cpmax(2)

Second maximum drug concentration in the plasma

tmax(1)

Time of first maximum drug concentration in the plasma

tmax(2)

Time of second maximum drug concentration in the plasma

Copyright information

© Plenum Publishing Corporation 1987

Authors and Affiliations

  • Rebecca L. Oberle
    • 1
  • Gordon L. Amidon
    • 1
  1. 1.College of PharmacyThe University of MichiganAnn Arbor