Elucidation of the biochemical basis for a clinical drug–drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha

Autor:	Steven G. Terra, Mark A. West, Charles J. Rotter, Amit S. Kalgutkar, Robert L. Walsky, Bo Feng, Manthena V.S. Varma, Renato J. Scialis, Kosea S. Frederick, Omar L. Francone, James R. Gosset, Theunis C. Goosen, Danny Chen
Rok vydání:	2013
Předmět:	Agonist Time Factors medicine.drug_class Health Toxicology and Mutagenesis Atorvastatin Cmax Peroxisome proliferator-activated receptor Alpha (ethology) Pharmacology Hydroxylation Toxicology Benzoates Biochemistry Madin Darby Canine Kidney Cells Dogs Cytochrome P-450 Enzyme System Pharmacokinetics medicine Animals Cytochrome P-450 Enzyme Inhibitors Humans Drug Interactions PPAR alpha Pyrroles chemistry.chemical_classification Sulfonamides Chemistry Area under the curve Membrane Transport Proteins nutritional and metabolic diseases General Medicine Benzoic Acid HEK293 Cells Heptanoic Acids Peroxisome proliferator-activated receptor alpha Oxidation-Reduction medicine.drug
Zdroj:	Xenobiotica. 43:963-972
ISSN:	1366-5928 0049-8254
DOI:	10.3109/00498254.2013.791004
Popis:	1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans. 2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778875 (1.0 mg QD) on days 5-12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778875. Subjects in group B (n = 29) received CP-778875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5-12. 3. Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778875. CP-778875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin. 4. Inhibition of organic anion transporting polypeptide 1B1 by CP-778875 (IC50 = 2.14 ± 0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin.
Databáze:	OpenAIRE
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