TY - JOUR T1 - PHARMACOKINETICS AND METABOLISM OF TESAGLITAZAR, A NOVEL DUAL-ACTING PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST, AFTER A SINGLE ORAL AND INTRAVENOUS DOSE IN HUMANS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 923 LP - 929 VL - 32 IS - 9 AU - H. Ericsson AU - B. Hamrén AU - S. Bergstrand AU - M. Elebring AU - L. Fryklund AU - M. Heijer AU - K. P. Öhman Y1 - 2004/09/01 UR - http://dmd.aspetjournals.org/content/32/9/923.abstract N2 - The pharmacokinetics of tesaglitazar (GALIDA), a novel dual-acting peroxisome proliferator-activated receptor α and γ agonist, were studied in eight healthy male subjects. The subjects initially received either a single oral or intravenous (i.v.) dose of 1 mg of [14C]tesaglitazar. After a washout period, they received 1 mg of nonlabeled tesaglitazar via the alternative administration route. Serial blood samples and complete urine and feces were collected until 336 h postdose. Tesaglitazar absorption was rapid, with maximum plasma concentration (Cmax) at ∼1 h postdose, and the absolute bioavailability was approximately 100%, suggesting no, or negligible, first-pass metabolism. Mean plasma clearance was 0.16 l/h and the volume of distribution at steady state was 9.1 liters. After either route of administration, the plasma concentration-time profiles of radioactivity and tesaglitazar were virtually identical, indicating low systemic metabolite concentrations and formation rate limitation of metabolite elimination. The elimination half-life of radioactivity and tesaglitazar was ∼45 h. Radioactivity recovery was complete in all subjects, with mean values of 99.9% (i.v.) and 99.6% (oral). Tesaglitazar was mainly metabolized before excretion, and most radioactivity (91%) was recovered in urine. Approximately 20% of the dose was recovered unchanged after either administration route, resulting in a renal clearance of 0.030 l/h. Most of the radioactivity in urine was identified as acyl glucuronide of tesaglitazar. Plasma protein binding of tesaglitazar was high (∼99.9%), and the mean blood-plasma partitioning ratio was 0.66, suggesting low affinity for red blood cells. There was no indication of partial inversion of the (S)-enantiomer to the corresponding (R)-form. Tesaglitazar was well tolerated. The American Society for Pharmacology and Experimental Therapeutics ER -