Influence of renal function on the pharmacokinetics of diacerein after a single oral dose.
The pharmacokinetics of diacetylrhein following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups of 8 patients with mild or severe renal insufficiency. Statistical analysis using a Kruskal-Wallis rank sum test showed a significant difference between the three groups for the following parameters. In severely uraemic patients, median AUC0-infinity was multiplied by a factor of about 2: 40.5 mg.h/l versus 21.3 mg.h/l in healthy subjects, P = 0.04; and t1/2 was prolonged by the same factor: 9.6 h versus 4.3 h in the control group, P = 0.003. Apparent drug availability and renal clearance assessed through urinary data decreased with renal failure, respectively: 14.5% and 0.045 l/h versus 35.4% (P = 0.01) and 0.13 l/h (P = 0.008) in healthy subjects. Amounts of glucuro- and sulpho-conjugates in urine were lower in severely uraemic patients. Intermediate values were observed for mildly uraemic patients. Other parameters: lag time, Cmax, tmax, Vss/F, urinary glucuro- to sulpho-conjugate ratios did not change significantly. Apparent total clearance of rhein was poorly correlated with creatinine clearance and this was related to a decrease of non-renal clearance of rhein in renal insufficiency. It was concluded that, from a pharmacokinetic point of view, a reduction (50%) in the initial dosage of diacerein should be considered in severe renal failure.
Debord
P
P
Department of Pharmacotoxicology, Avicenne Hospital, Bobigny, France.
Louchahi
K
K
Tod
M
M
Cournot
A
A
Perret
G
G
Petitjean
O
O
D000328:Adult; D000368:Aged; D000880:Anthraquinones / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors
D000880:Anthraquinones; D000894:Anti-Inflammatory Agents, Non-Steroidal; C025292:diacerein; D009247:NADH, NADPH Oxidoreductases; C020491:rhein