Johan Gabrielsson

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

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.

A physiological pharmacokinetic model for morphine disposition in the pregnant rat

A physiological model was used to examine the disposition of morphine in the pregnant rat. In the model was incorporated an expression of both a linear and a nonlinear binding term of morphine to the maternal muscular tissue. Furthermore, the experimental data suggested that a diffusion-limited transport of morphine occurred across the placenta. Morphine showed a relatively high partition into the maternal kidney and muscle tissues. The concentration of morphine in the foetus was about 1.5 times higher than that of the maternal plasma, whereas the foetal brain concentration was about 4 times higher than that of the maternal plasma. The influence on morphine disposition by changes in both the tissue binding of the maternal muscle and the placental plasma flow was explored by model simulations. Due to the diffusionlimited transport of morphine across the placenta, a change in the placental plasma flow would only have an effect on the concentration-time profile of morphine in the foetal tissues if the plasma flow approached and became less than the diffusion clearance across the placenta. An increase in the partition of morphine into the maternal muscle produced an increase in the terminal half-life in all tissues including the foetus.

A physiologically based pharmacokinetic model for theophylline disposition in the pregnant and nonpregnant rat

There are numerous studies which examine the disposition of theophylline from a traditional point of view. Information about the behaviour of drugs, including theophylline, is, however, very scarce when investigating the kinetics by means of a physiological flow model. This study is concerned with the development of a predictive analytical model for the pharmacokinetics of theophylline in nonpregnant and pregnant rats. This model postulates that specific organ or tissue masses may be simulated by compartments whose elements have physiological properties, e.g., tissue volumes, blood flow, and metabolic activity. A model has been developed that has blood, brain, hepatic, muscular, pulmonary, renal, and fetal tissues. With few exceptions, the agreement was good between predicted and calculated tissue data in the pregnant and nonpregnant rats. Finally, model simulations were performed to investigate the impact of different pulmonary extraction ratios on the concentration-time profile of theophylline in a “hypothetical” human patient.

A pharmacokinetic model of intravenously administered hyaluronan in sheep

Hyaluronan (HA; hyaluronic acid) is produced in the interstitium and reaches the blood circulation through the lymph. It is rapidly eliminated by means of specific receptors on liver endothelium. The elimination characteristics of intravenously administered HA were studied in 10 conscious sheep at the normal plasma HA concentration by injection of a 3H-labeled tracer and at a very high concentration by an i.v. infusion of unlabeled HA and simultaneous injection of a tracer dose of 3H-labeled HA. At a normal plasma HA concentration (0.12 ± 0.05 µg/ml; range, 0.072–0.228 µg/ml), the apparent T1/2 of 3H-HA was 5.3 ± 1.1 min (range, 3.3–6.5 min). At higher plasma concentrations (range, 1.83–3.35 µg/ml), the apparent T1/2 was considerably prolonged (range, 18.2–43.5 min). A one-compartment, nonlinear model was fitted to data obtained from the bolus-infusion study of unlabeled HA. The Michaelis–Menten constant, Km, was 0.12 ± 0.04 µg/ml, indicating that a deviation from linear kinetics will occur when the normal plasma concentration is exceeded. The Vmax was 0.062 ± 0.009 µg/ml/min. Three-dimensional surface plots showed that the plasma HA concentration and the total hepatic plasma flow influence the apparent metabolic clearance, extraction ratio, turnover, and T1/2 of intravenously injected hyaluronan. There was a high correlation between T1/2 as measured by the injected 3H-HA and T1/2 calculated from the model (r = 0.96).

Constant rate of infusion--improvement of tests for teratogenicity and embryotoxicity.

Sodium salicylate was used as a model substance to investigate whether the embryotoxic effects on rat fetuses varies between two modes of administration. A marked increase in fetal adverse effects was observed at analgetic doses with the once-a-day bolus regimen compared to the constant rate input. The difference was less marked at antirheumatic levels.