In vitro prediction of clinical drug interactions with CYP3A substrates: we are not there yet.
In 1973, Malcolm Rowland and associates described an approach to predicting clinical pharmacokinetic drug-drug interactions (DDIs) using an inhibition constant determined in vitro (Ki) together with anticipated inhibitor exposure in vivo ([I]). Despite numerous modifications and refinements of the core model over the following 40 years, we still have not achieved a predictive paradigm having accuracy sufficient to justify bypassing all, or even most, clinical DDI studies in the course of drug development.
Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts, USA.
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Greenblatt
D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D015507:Drugs, Investigational / Q000009:adverse effects*; D006801:Humans
D065692:Cytochrome P-450 CYP3A Inhibitors; D015507:Drugs, Investigational; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human