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Vol. 30, Issue 12, 1512-1522, December 2002
School of Pharmacy and Pharmaceutical Sciences, University of
Manchester, Manchester, United Kingdom (A.G., J.B.H.); and Department
of Mechanism and Extrapolation Technologies, GlaxoSmithKline, Welwyn,
Hertfordshire, United Kingdom (S.E.C.)
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.
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