Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model

Abstract

The disposition of pethidine (meperidine) in the pregnant rat is described by means of a physiological flow model. The model includes arterial and venous blood, brain, fat, fetal, hepatic, intestinal, muscular, pulmonar, and renal tissues. The concentration-time profiles of pethidine calculated by the model are consistent with experimental data, except for the brain and renal tissues, where the model predicts initially higher concentrations. Simulations are carried out to further explore the contribution from different organs on the kinetics in blood and tissues. The tissue-to-blood partition coefficients vary over a range from 5 to 316, where fat has the lowest and liver the highest after a correction is made due to hepatic extraction. Rapid uptake occurs into highly perfused organs such as brain, kidneys, liver, and lungs, followed by fetus, intestines, muscle, and fat. Data indicate no marked membrane resistance to pethidine of the investigated organs, except for fetal tissues, but rather a perfusion-limited uptake. Simulations suggest that muscles and adipose tissue play an important role in the rat, becoming the major reservoir of drug during the intermediate and terminal elimination phase, respectively. Volume of distribution and the biological half-life agree with reported findings. Pethidine is subject to a high systemic blood clearance, which exceeds the total hepatic blood flow in the rat. No degradation of pethidine is found in blood, and therefore a pulmonary expression for pethidine clearance is added as a potential source of pethidine elimination. The elimination of pethidine after a single i.v. bolus dose is found to be dependent on simulated changes in cardiac output and hepatic blood flow. A simulation is performed with the scaled model to mimic the human concentration-time profiles in maternal blood and brain tissues and fetal tissue during repetitive doses of pethidine.