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Research ArticleArticle

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

H. Ericsson, B. Hamrén, S. Bergstrand, M. Elebring, L. Fryklund, M. Heijer and K. P. Öhman
Drug Metabolism and Disposition September 2004, 32 (9) 923-929;
H. Ericsson
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B. Hamrén
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S. Bergstrand
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M. Elebring
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L. Fryklund
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M. Heijer
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Abstract

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.

Footnotes

  • ABBREVIATIONS: AUC, area under the plasma concentration-time curve; CL, plasma clearance; CLR, renal clearance; Cmax, maximum plasma concentration; tmax, time to maximum plasma concentration; t1/2, elimination half-life; LC, liquid chromatography; LOQ, limit of quantification; CV, coefficient of variation; UGT, UDP-glucuronosyltransferase; P450, cytochrome P450; DDI, drug-drug interaction.

    • Received January 12, 2004.
    • Accepted June 1, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (9)
Drug Metabolism and Disposition
Vol. 32, Issue 9
1 Sep 2004
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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
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Research ArticleArticle

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

H. Ericsson, B. Hamrén, S. Bergstrand, M. Elebring, L. Fryklund, M. Heijer and K. P. Öhman
Drug Metabolism and Disposition September 1, 2004, 32 (9) 923-929;

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Research ArticleArticle

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

H. Ericsson, B. Hamrén, S. Bergstrand, M. Elebring, L. Fryklund, M. Heijer and K. P. Öhman
Drug Metabolism and Disposition September 1, 2004, 32 (9) 923-929;
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