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. (November 2013)

• Record Type: Journal Article
• Authors: Kalgutkar, Amit S.; Chen, Danny; Varma, Manthena V.; Feng, Bo; Terra, Steven G.; Scialis, Renato J.; Rotter, Charles J.; Frederick, Kosea S.; West, Mark A.; Goosen, Theunis C.; Gosset, James R.; Walsky, Robert L.; Francone, Omar L.
• Is Part Of: Xenobiotica. Volume 43:Number 11(2013:Nov.)
• Page Start: 963
• Page End: 972
• Publication Date: 2013-11
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2013.791004
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. <?ri?>5-(<italic>N</italic>-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), 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-778 875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans.</p> <p>2. <?ri?>The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778 875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (<italic>n</italic> = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778 875 (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-778 875. Subjects in group B (<italic>n</italic> = 29) received CP-778 875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5–12.</p> <p>3. <?ri?>Mean maximum serum concentration (<italic>C</italic><sub>max</sub>) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778 875. Statistically significant increases in the systemic exposure of <italic>ortho</italic>- and <italic>para</italic>-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778 875. CP-778 875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin.</p> <p>4. <?ri?>Inhibition of organic anion transporting polypeptide 1B1 by CP-778 875 (IC<sub>50</sub> = 2.14 ±<!-- -->0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778 875 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.</p> </abstract>