The effect of erythromycin on the pharmacokinetics of rosuvastatin.

RATIONALE OBJECTIVE: To examine in vivo the effect of erythromycin on the pharmacokinetics of rosuvastatin [an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase]. Erythromycin is a potent inhibitor of CYP3A4 that markedly increases circulating levels of some other HMG-CoA reductase inhibitors. METHODS: In this randomised, double-blind, two-way cross-over, placebo-controlled trial 14 healthy volunteers were given 500 mg erythromycin or placebo four times daily for 7 days. A single dose of 80 mg rosuvastatin was co-administered on day 4 of dosing. Plasma concentrations of rosuvastatin and active and total HMG-CoA reductase inhibitors were measured up to 96 h after dosing. RESULTS: Eleven volunteers had data available from both dosing periods. There was no increase in rosuvastatin plasma exposure following co-administration with erythromycin compared to placebo. In fact, following co-administration with erythromycin, rosuvastatin geometric least square mean AUC((0-t)) and C(max) were 20% and 31%, respectively, lower than with placebo. Individual treatment ratios for AUC((0-t)) ranged from 0.48 to 1.17, and for C(max) ranged from 0.33 to 2.19. Essentially all of the circulating active HMG-CoA reductase inhibitors and most (>94%) of the total inhibitors were accounted for by rosuvastatin. Erythromycin did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Erythromycin did not produce any increase in rosuvastatin plasma exposure. This indicates that CYP3A4 metabolism is not an important clearance mechanism for rosuvastatin, a result consistent with previous findings. The small decreases in rosuvastatin AUC((0-t)) and C(max) that occurred as a consequence of short-term treatment with erythromycin are unlikely to have relevance to long-term treatment with rosuvastatin.

Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic impairment.

OBJECTIVE: To assess the effect of chronic hepatic impairment on rosuvastatin disposition, pharmacodynamic activity and tolerability. METHODS: This was an open-label, non-randomised, parallel-group trial. Six subjects were enrolled in each of three hepatic-function strata: Child-Pugh class A (CP-A, mild impairment), Child-Pugh class B (CP-B, moderate impairment) and normal hepatic function; the latter two strata were age, weight, race, sex and smoking history matched. All subjects were given rosuvastatin 10 mg for 14 days. RESULTS: In subjects with CP-A, and in four of six subjects with CP-B, rosuvastatin steady-state AUC(0-24) and C(max) were similar to subjects with normal hepatic function (geometric mean values 60.7 ng h/ml and 6.02 ng/ml, respectively). Two of six subjects with CP-B who had the highest CP scores (i.e. the highest degrees of hepatic impairment) had the highest AUC(0-24) (128 ng h/ml and 242 ng h/ml) and C(max) (23.4 ng/ml and 96.7 ng/ml) values. Low-density lipoprotein cholesterol (LDL-C) was decreased in all strata, but the response was more variable in the CP-B group. Rosuvastatin was well tolerated, and the safety profile was similar in subjects with hepatic impairment and normal hepatic function. CONCLUSION: In most subjects with mild-to-moderate hepatic impairment, the steady-state pharmacokinetics of rosuvastatin were similar to subjects with normal hepatic function (more extensive hepatic impairment may increase systemic exposure to rosuvastatin), and most had LDL-C reductions similar to subjects with normal hepatic function.

The effect of fluconazole on the pharmacokinetics of rosuvastatin.

OBJECTIVE: To examine the effect of fluconazole, a potent inhibitor of CYP2C9 and CYP2C19, on the pharmacokinetics of rosuvastatin in healthy volunteers. Significantly increased plasma concentrations of fluvastatin have been observed following co-administration with fluconazole. METHODS: This was a randomised, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers ( n=14) were given fluconazole 200 mg or matching placebo once daily for 11 days; rosuvastatin 80 mg was co-administered on day 8 of dosing. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 96 h post-dose. RESULTS: Following co-administration with fluconazole, rosuvastatin geometric least-square mean area under the plasma concentration-time curve (AUC(0-t)) and peak plasma concentration (C(max)) were increased by 14% and 9%, respectively, compared with placebo (90% confidence intervals for the treatment ratios: 0.967 to 1.341 and 0.874 to 1.355, respectively). Individual treatment ratios for AUC(0-t) ranged from 0.59 to 2.23, and for C(max) ranged from 0.52 to 2.28. The limited data available for the N-desmethyl metabolite show that geometric mean C(max) was decreased by approximately 25% compared with placebo. Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (>90%) of the total inhibitors. Fluconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Fluconazole produced only small increases in rosuvastatin AUC(0-t) and C(max), which were not considered to be of clinical relevance. The results support previous in-vitro findings that CYP2C9 and CYP2C19 metabolism is not an important clearance mechanism for rosuvastatin.

The pharmacokinetics of Casodex in laboratory animals.

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs. 2. The binding of 14C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values greater than 95%; in dog there was evidence for decreased binding at concentrations greater than 12 micrograms/ml. 3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1 mg/kg to 10% and 12% at 250 mg/kg; in dog bioavailability decreased from 100% at 0.1 mg/kg to 31% at 100 mg/kg. 4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10 mg/kg but not at 250 mg/kg; in dog appreciable accumulation (9-12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10 mg/kg, but at 100 mg/kg the accumulation ratio was much lower (4-fold).

Determination of synthetic growth promoters in bile.

To monitor the use of synthetic growth promoting hormones in red meat animals requires a sensitive and rapid method of analysis. This paper describes the development of such a method for these agents in bile, based on a high pressure liquid chromatographic purification procedure with detection and estimation by radioimmunoassay.