| Efforts for the rapid screening of drug adsorp-| tion metabolism have intensified as the imports tance and relevance of the parameters for drug discovery have become more apparent | with every failed and recalled drug. The cyto-| chrome P450 (CYP) enzymes metabolize xe-I nobiotics and evolved as a defense against ac-I cidentally ingested toxic compounds. Drug pharmacokinetics are modulated in part by metabolism and patients on multi-drug regimens can experience unexpected changes, both positive and negative, in drug mean residence time and maximum serum levels. Drug I inhibition of CYPs can lead to increased drug | levels and increased risk of toxic side effects. | Several high-throughput assays for test comI pound inhibition of CYPs have been reported I (36-38).Most are based on changes in the flur orescence of a known CYP substrate and speI cificCYP isoform inhibition in the presence of I test compounds. Increased CYP activity can | result in toxicity as well. The nuclear hormone I receptor CAR controls the expression-based response to a class of molecules called the I "phenobarbitol-like inducers." In the mouse, these molecules are known to regulate the ex-I pression of a particular cytochrome P450 I Cyp2bl0. Cocaine causes acute liver toxicity in I mice previously exposed to CAR agonists, and I this toxicity is absent in CAR knockout ani-1 mals (39). CYP gene induction, modulated at I least in part through xenobiotic binding to the nuclear hormone receptors such as CAR, can K also result in more rapid drug clearance rates, lower serum concentration, and decreased i efficacy. Thus, drug-drug interactions are im-I portant in both toxicity and efficacy. In addi-1 tion to metabolic degradation and inactiva-■j tion, drug efficacy is reduced by excretion.
Another protein specifically targeted for sec-W\ ondaiy pharmacological screening is the ATP-
dependent pump, P-glycoprotein, PGP, (encoded by ABCB1, also known as MDR1), is a broad specificity pump that is responsible for efflux of compounds from the intestine, thus blocking their uptake. P-glycoprotein is over-expressed in some tumor cells and is responsible for cancer drug resistance and is part of the blood-brain barrier where it helps protect the brain from exogenous agents. P-glycoprotein expression is regulated by the orphan nuclear receptor SXR (other names are PXR, PAR, PRR or NR112). Taxol activates the SXR receptor, increasing the expression of both P-glycoprotein and the cytochrome P450 iso-forms CYP2C8 and CYP3A4 (40). Taxol's efficacy is decreased by both increased excretion and metabolism through PGP and CYP2C8/CYP3A4 induction, respectively. Reporter assays for lead compound effect on CAR and SXR activity could add useful information to drug development programs by flagging compoundsfor possible drug-drug interaction and metabolic liabilities.
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