mechanism-based inactivator of CYP2C8 (Ogilvie et al., 2006; Shitara et al.,
2004). Therefore, the impact of gemfibrozil on cerivastatin pharmacokinetics is
likely caused by a combination of hepatic uptake and CYP2C8 inhibition. This
example clearly demonstrates the need to thoroughly examine the roles of CYP-
mediated metabolism and drug transporters in drug disposition.
References
Backlund M, Ingelman-Sundberg M. Regulation of aryl hydrocarbon receptor signal
transduction by protein tyrosine kinases. Cell Signal 2005;17:39–48.
Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly increases
plasma concentrations of cerivastatin. Clin Pharmacol Ther 2002;72:685–691.
Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly decreases and
gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites.
Clin Pharmacol Ther 2005;78:154–167.
Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma
concentrations and effects of oral midazolam. Clin Pharmacol Ther 1996;59:7–13.
Bauer S, Stormer E, Johne A, Kruger H, Budde K, Neumayer HH, Roots I, Mai I.
Alterations in cyclosporin a pharmacokinetics and metabolism during treatment with
St John’s wort in renal transplant patients. Br J Clin Pharmacol 2003;55:
203–211.
Bertilsson L, Hojer B, Tybring G, Osterloh J, Rane, A. Autoinduction of
carbamazepine metabolism in children examined by a stable isotope technique.
Clin Pharmacol Ther 1980;27:83–88.
Bidstrup TB, Bjornsdottir I, Sidelmann UG, Thomsen MS, Hansen KT. CYP2C8 and
CYP3A4 are the principal enzymes involved in the humanin vitrobiotransformation
of the insulin secretagogue repaglinide. Br J Clin Pharmacol 2003;56:
305–314.
Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP,
Miwa G, Ni L, Kumar G, McLeod J, Obach RS, Roberts S, Roe A, Shah A, Snikeris
F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA. The conduct ofin vitro
and in vivo drug–drug interaction studies: a pharmaceutical research and
manufacturers of America (PHARMA) perspective. Drug Metab Dispos 2003;31:
815–832.
Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, vanMeter CM, Ong ES, Evans,
RM. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev
1998;12:3195–3205.
Brown HS, Ito K, Galetin A, Houston JB. Prediction ofin vivodrug–drug interactions
fromin vitrodata: impact of incorporating parallel pathways of drug elimination and
inhibitor absorption rate constant. Br J Clin Pharmacol 2005;60:508–518.
Carnahan VE, Redinbo MR. Structure and function of the human nuclear xenobiotic
receptor PXR. Curr Drug Metab 2005;6:357–367.
Chien JY, Mohutsky MA, Wrighton SA. Physiological approaches to the prediction
of drug–drug interactions in study populations. Curr Drug Metab 2003;4:
347–356.
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