[Comparative pharmacokinetics of theophylline in hyperlipidemia in animals and humans]

The incidence of hereditary hyperlipidemia amounts to about 8% and rises when secondary causes of lipid metabolism disturbances are taken into consideration. In contemporary literature there is paucity of data on the influence of hyperlipidemia on pharmacokinetics of drugs. That is especially important in the case of drugs characterized by a narrow therapeutic index, such as theophylline, which can be administered to patients affected by an altered lipid status. The investigation was aimed at evaluating the feasibility of an animal model of hyperlipidemia for pharmacokinetic studies of theophylline in humans suffering from lipid metabolism disturbances. The study was carried out on male rabbits divided into two groups: a control and an experimental one, fed on a high-fat diet. Humans were also ascribed to two groups: controls and those affected by primary, mixed-form of hyperlipidemia. The animals were given theophylline intravenously in a single dose of 12 mg/kg, whereas humans received intravenously injected theophylline in a single dose of 3.5 mg/kg. Blood was sampled after 5, 10, 15, 30, 45 minutes and 1, 2, 4, 6, 8, 12, 24 hours following theophylline administration. FPIA method was used to determine blood serum concentrations of theophylline (Tab. 1,3). The two-compartment open model for intravenous administration was applied for calculations. Considerable alterations of theophylline pharmacokinetics in humans suffering from mixed form of hyperlipidemia were observed (Tab. 4), whereas no marked changes were noted in animals with alimentary-induced hyperlipidemia (Tab. 2). In hyperlipidemic rabbits theophylline behaves as lipophilic agent, despite its poor penetration into the adipose tissue. A considerable decrease in area under the concentration-time curve of theophylline, increase in transfer constants as well as accelerated elimination of the drug were observed in humans with mixed form of hyperlipidemia. The behaviour of theophylline in hyperlipidemic rabbits was different from that in patients with mixed form of hyperlipidemia. Comparison of theophylline pharmacokinetics in hyperlipidemic animals and in human subjects revealed that an animal model of hyperlipidemia was inappropriate for studying the effect of lipid metabolism disturbances on pharmacokinetics of drugs as it is shown in the study on theophylline. This can be explained, to some extent, by different mechanisms of hyperlipidemia in rabbits and in humans. Hyperlipidemia in rabbits was induced by alimentary factors, while in humans lipid metabolism disturbances were of primary origin. Basing on the results of the present study it may be suggested that there are no general rules for anticipating the influence of hyperlipidemia on the pharmacokinetics of drugs in various organisms. Therefore, it is most likely that studies on the influence of hyperlipidemia on the pharmacokinetics of drugs should be performed for every particular drug separately.