title: 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-778875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha.
abstract: 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.
authors: Pharmacokinetics, Dynamics and Metabolism Department , Pfizer Inc., Cambridge, MA , USA .
authors: Amit S
authors: AS
authors: Kalgutkar
authors: Danny
authors: D
authors: Chen
authors: Manthena V
authors: MV
authors: Varma
authors: Bo
authors: B
authors: Feng
authors: Steven G
authors: SG
authors: Terra
authors: Renato J
authors: RJ
authors: Scialis
authors: Charles J
authors: CJ
authors: Rotter
authors: Kosea S
authors: KS
authors: Frederick
authors: Mark A
authors: MA
authors: West
authors: Theunis C
authors: TC
authors: Goosen
authors: James R
authors: JR
authors: Gosset
authors: Robert L
authors: RL
authors: Walsky
authors: Omar L
authors: OL
authors: Francone
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D019817:Benzoic Acid / Q000737:chemistry / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004347:Drug Interactions; D057809:HEK293 Cells; D006538:Heptanoic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D026901:Membrane Transport Proteins / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists*; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C000588958:5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methylbenzoic acid; D001565:Benzoates; D065607:Cytochrome P-450 Enzyme Inhibitors; D006538:Heptanoic Acids; D026901:Membrane Transport Proteins; D047493:PPAR alpha; D011758:Pyrroles; D013449:Sulfonamides; D019817:Benzoic Acid; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin