RT Journal Article
SR Electronic
T1 Quinidine and Haloperidol as Modifiers of CYP3A4 Activity: Multisite Kinetic Model Approach
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1512
OP 1522
DO 10.1124/dmd.30.12.1512
VO 30
IS 12
A1 Aleksandra Galetin
A1 Stephen E. Clarke
A1 J. Brian Houston
YR 2002
UL http://dmd.aspetjournals.org/content/30/12/1512.abstract
AB The selection of appropriate substrates for investigating the potential inhibition of CYP3A4 is critical as the magnitude of effect is often substrate-dependent, and a weak correlation is often observed among different CYP3A4 substrates. This feature has been attributed to the existence of multiple binding sites and, therefore, relatively complex in vitro data modeling is required to avoid erroneous evaluation and to allow prediction of drug-drug interactions. This study, performed in lymphoblast-expressed CYP3A4 with oxidoreductase, provides a systematic comparison of the effects of quinidine (QUI) and haloperidol (HAL) as modifiers of CYP3A4 activity using a selection of CYP3A4 substrates: testosterone (TST), midazolam (MDZ), nifedipine (NIF), felodipine (FEL), and simvastatin (SV). The effect of QUI and HAL on CYP3A4-mediated pathways was substrate-dependent, ranging from potent inhibition of NIF (Ki = 0.25 and 5.3 μM for HAL and QUI, respectively), weak inhibition (TST), minimal effect (HAL on MDZ/SV) to QUI activation of FEL and SV metabolism. Inhibition of TST metabolite formation occurred but its autoactivation properties were maintained, indicating binding of a QUI/HAL molecule to a distinct effector site. Various multisite kinetic models have been applied to elucidate the mechanism of the drug-drug interactions observed. Kinetic models with two substrate-binding sites have been found to be appropriate to a number of interactions, provided the substrates show hyperbolic (MDZ, FEL, and SV) or substrate inhibition kinetic properties (NIF). In contrast, a three-site model approach is required for TST, a substrate showing positive cooperativity in its binding to CYP3A4. The American Society for Pharmacology and Experimental Therapeutics