Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers.
BACKGROUND
Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor, or statin, that has been developed for the treatment of dyslipidemia.


OBJECTIVE
This study assessed the metabolism, excretion, and pharmacokinetics of a single oral dose of radiolabeled rosuvastatin ([14C]-rosuvastatin) in healthy volunteers.


METHODS
This was a nonrandomized, open-label, single-day trial. Healthy adult male volunteers were given a single oral dose of [14C]-rosuvastatin 20 mg (20 mL [14C]-rosuvastatin solution, nominally containing 50 microCi radioactivity). Blood, urine, and fecal samples were collected up to 10 days after dosing. Tolerability assessments were made up to 10 days after dosing (trial completion) and at a follow-up visit within 14 days of trial completion.


RESULTS
Six white male volunteers aged 36 to 52 years (mean, 43.7 years) participated in the trial. The geometric mean peak plasma concentration (C(max)) of rosuvastatin was 6.06 ng/mL and was reached at a median of 5 hours after dosing. At C(max), rosuvastatin accounted for approximately 50% of the circulating radioactive material. Approximately 90% of the rosuvastatin dose was recovered in feces, with the remainder recovered in urine. The majority of the dose (approximately 70%) was recovered within 72 hours after dosing; excretion was complete by 10 days after dosing. Metabolite profiles in feces indicated that rosuvastatin was excreted largely unchanged (76.8% of the dose). Two metabolites-rosuvastatin-5S-lactone and N-desmethyl rosuvastatin-were present in excreta. [14C]-rosuvastatin was well tolerated; 2 volunteers reported 4 mild adverse events that resolved without treatment.


CONCLUSIONS
The majority of the rosuvastatin dose was excreted unchanged. Given the absolute bioavailability (20%) and estimated absorption (approximately 50%) of rosuvastatin, this finding suggests that metabolism is a minor route of clearance for this agent.
Martin
Paul D
PD
AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom. paul.martin@astrazeneca.com
Warwick
Mike J
MJ
Dane
Aaron L
AL
Hill
Steve J
SJ
Giles
Petrina B
PB
Phillips
Paul J
PJ
Lenz
Eva
E
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002247:Carbon Isotopes; D002851:Chromatography, High Pressure Liquid; D005464:Fluorobenzenes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006207:Half-Life; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D002247:Carbon Isotopes; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium