Pharmacokinetics and metabolism of tesaglitazar, a novel dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, after a single oral and intravenous dose in humans.
The pharmacokinetics of tesaglitazar (GALIDA), a novel dual-acting peroxisome proliferator-activated receptor alpha and gamma 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 [(14)C]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 (C(max)) at approximately 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 approximately 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 ( approximately 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.
Ericsson
H
H
Department of Experimental Medicine, Astra-Zeneca R&D, Mölndal, Sweden. Hans.ericsson@astrazeneca.com
Hamrén
B
B
Bergstrand
S
S
Elebring
M
M
Fryklund
L
L
Heijer
M
M
Ohman
K P
KP
D000284:Administration, Oral; D000328:Adult; D000476:Alkanesulfonates / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002250:Carbon Radioisotopes; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005243:Feces / Q000737:chemistry; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D047492:Peroxisome Proliferator-Activated Receptors / Q000008:administration & dosage* / Q000819:agonists*; D010666:Phenylpropionates / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors
D000476:Alkanesulfonates; D002250:Carbon Radioisotopes; D047492:Peroxisome Proliferator-Activated Receptors; D010666:Phenylpropionates; C501413:tesaglitazar