期刊
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 59
卷 59, 期 -, 页码 507-536出版社
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-010818-021909
关键词
cytochrome P450 enzymes; drug transporters; drug-drug interactions; healthy volunteers; physiologically based pharmacokinetic modeling; validation
Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug-drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies.
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