On the role of pharmacokinetics in integrating results from in vivo and in vitro studies.
Our knowledge of the biological effects of foreign compounds has been developed from many different kinds of studies. In vitro studies are usually designed to evaluate the plausibility of hypothetical events by which the foreign compound may cause a response. Because in vitro studies are designed to evaluate individual mechanisms and events, however, no single in vitro study can provide all the information needed to understand fully the mechanisms of all responses caused by a drug and the in vivo factors that may modulate them. For example, one ste of studies in vitro may provide an understanding of the enzymes that metabolize the biologically active foreign compound in various organs and ideally provide estimates of the intrinsic clearances of the enzymes in the organs. Another set of in vitro studies may provide information about the kinetics of the action of various biologically active substances, including perhaps metabolites of the parent foreign compound, on potential receptor sites in various organs. Neither set of studies by themselves, however, provides assurance that the concentrations required to evoke the response in vitro are actually attainable in vivo. Pharmacokinetic studies in vitro thus provide the necessary link between the two types of in vitro experiment. This paper discusses the two pharmacokinetic approaches currently being used, and illustrates the strength and weakness of each. It also discusses the ways in which in vitro studies clarify some of the uncertainties that may arise in the application of the pharmacokinetic approaches. Further, it suggests some possible mechanisms of action of drugs that may result in delayed responses.
D004798:Enzymes / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D004798:Enzymes; D004364:Pharmaceutical Preparations