In vitro approaches to predicting drug interactions in vivo.
In vitro metabolic models using human liver microsomes can be applied to quantitative prediction of in vivo drug interactions caused by reversible inhibition of metabolism. One approach utilizes in vitro Ki, values together with in vivo values of inhibitor concentration to forecast in vivo decrements of clearance caused by coadministration of inhibitor. A critical limitation is the lack of a general scheme for assigning intrahepatic exposure of enzyme to inhibitor or substrate based only on plasma concentration; however, the assumption that plasma protein binding necessarily restricts hepatic uptake is not tenable. Other potential limitations include: flow-dependent hepatic clearance, "mechanism-based" chemical inhibition, concurrent induction, or a major contribution of gastrointestinal P450-3A isoforms to presystemic extraction. Nonetheless, the model to date has provided reasonably accurate forecasts of in vivo inhibition of clearance of several substrates (desipramine, terfenadine, triazolam, alprazolam, midazolam) by coadministration of selective serotonin reuptake-inhibitor antidepressants and azole antifungal agents. Such predictive models deserve further evaluation, since they may ultimately yield more cost-effective and expeditious screening for drug interactions, with reduced human drug exposure and risk.
von Moltke
L L
LL
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA. lvonmoltke@infonet.tufts.edu
Greenblatt
D J
DJ
Schmider
J
J
Wright
C E
CE
Harmatz
J S
JS
Shader
R I
RI
D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases; D001393:Azoles / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004064:Digestive System / Q000201:enzymology; D004347:Drug Interactions; D006801:Humans; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D008954:Models, Biological; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010599:Pharmacokinetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics
D000928:Antidepressive Agents; D000935:Antifungal Agents; D001189:Aryl Hydrocarbon Hydroxylases; D001393:Azoles; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D010089:Oxidoreductases, N-Demethylating; D017367:Selective Serotonin Reuptake Inhibitors