Pharmacokinetic considerations consequences

Many factors have a profound influence on the pharmacokinetics of drugs and consequently on a patient s pharmacological response (Box 33-1). For example, the consideration of the patient s history, with particular emphasis on theirpathophysiological state and adjunct drug therapy, is essential at the initiation of drug therapy and TDM. Other important factors include how a drug is absorbed, distributed, metabolized, cleared by the Liver, biotransformed, and excreted. 

The FDA definition given in CFR 21.320.1 refers to bioavailability as the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action. This phrasing has led to a considerable confusion and sometimes misinterpretation of published data [19], and, as a consequence, the terms oral bioavailability and oral absorption are often used interchangeably in the scientific literature [112]. However, in the context of a more mechanistic interpretation of pharmacokinetic data, the separation of the two expressions is desired. 

Finally, the successful application of congener analysis in casework requires considerable experience not only regarding laboratory analysis but also controlled drinking experiments. Studies of this kind furnish the information needed about the pharmacokinetics of specific congener, their interactions with ethanol metabolism and urine/blood relationships. Consequently, much basic research is necessary before embarking in actual casework, this expertise, at the present moment is available at only a few institutes of legal medicine on Germany. 

Although the pharmacodynamic effect is primarily a function of the concentration of a drug at the site of action and the affinity of the drug for the receptors, time-dependent processes such as ADME also influence the observed effect. Consequently, the pharmacodynamic effect is also a function of time, especially under in vivo conditions where drug molecules may not equilibrate rapidly with the biophase. Recently, relationships between plasma concentrations of drugs and pharmacodynamic effects have received considerable attention. The mathematical analysis of the relationships between pharmacokinetics and pharmacodynamics is often termed... 

The effects of probenecid on the pharmacokinetics of four doses of oseltamivir have been studied in healthy Thai adults [265. The median half-lives were 1.0 hour for oseltamivir and 5.1 hours for oseltamivir carbox-ylate. In one subject there was markedly reduced hydrolysis of oseltamivir to its car-boxylate, consistent with impaired carboxylesterase activity. Co-administration of probenecid resulted in a mean 40% reduction in the apparent volume of distribution of oseltamivir carboxylate and a 61% reduction in its renal ehmination, with a consequent 154% increase in the AUC. The AUC increase in saliva was about three times less than the AUC increase in plasma. The authors concluded that probenecid coadministration may reduce oseltamivir dose requirements considerably. 

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