Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers.
BACKGROUND
Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. The results of clinical trials suggest that it is effective and well tolerated.


OBJECTIVE
The goals of this study were to determine the absolute bioavailability of an oral dose of rosuvastatin and to describe the intravenous pharmacokinetics of rosuvastatin in healthy volunteers.


METHODS
This was a randomized, open-label, 2-way crossover study consisting of 2 trial days separated by a > or =7-day washout period. Healthy male adult volunteers were given a single oral dose of rosuvastatin 40 mg on one trial day and an intravenous infusion of rosuvastatin 8 mg over 4 hours on the other. Pharmacokinetic and tolerability assessments were conducted up to 96 hours after dosing. A 3-compartment pharmacokinetic model was fitted to the plasma concentration-time profiles obtained for each volunteer after intravenous dosing.


RESULTS
Ten white male volunteers entered and completed the trial. Their mean age was 35.7 years (range, 21-51 years), their mean height was 177 cm (range, 169-182 cm), and their mean body weight was 77.6 kg (range, 68-85 kg). The absolute oral bioavailability of rosuvastatin was estimated to be 20.1%,and the hepatic extraction ratio was estimated to be 0.63. The mean volume of distribution at steady state was 134 L. Renal clearance accounted for approximately 28% of total plasma clearance (48.9 L/h). Single oral and intravenous doses of rosuvastatin were well tolerated in this small number of healthy male volunteers.


CONCLUSIONS
The absolute oral bioavailability of rosuvastatin in these 10 healthy volunteers was approximately 20%, and absorption was estimated to be 50%. The volume of distribution at steady state was consistent with extensive distribution of rosuvastatin to the tissues. The modest absolute oral bioavailability and high hepatic extraction of rosuvastatin are consistent with first-pass uptake into the liver after oral dosing. Rosuvastatin was cleared by both renal and nonrenal routes; tubular secretion was the predominant renal process.
Martin
Paul D
PD
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. paul.martin@astrazeneca.com
Warwick
Mike J
MJ
Dane
Aaron L
AL
Brindley
Charlie
C
Short
Tracy
T
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D005464:Fluorobenzenes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium