Pharmacokinetics of the PDGF-antagonist trapidil in patients with and without renal impairment.
The pharmacokinetics of the PDGF-antagonist trapidil and its major metabolite desethyl-trapidil (M 1) were studied in patients with and without renal failure after a single dose of 200 mg and following 4-day treatment with 200 mg t.i.d. Twenty patients were classified according to their renal function as assessed by creatinine clearance (C(Cr)) in group A: 133.7 +/- 30.3 ml/min (n = 8), group B: 63.6 +/- 15.4 ml/min (n = 6) and group C: 17.9 +/- 6.1 ml/min (n = 6), patients on hemodialysis were not enrolled. After the first dose maximal plasma concentrations of trapidil with 5.99 +/- 1.60 (A), 5.76 +/- 1.46 (B) and 5.63 +/- 1.53 micrograms/ml (C) were not different between groups, but somewhat lower on day 4 with 4.96 +/- 0.78 (A), 5.78 +/- 1.78 (B) and 5.47 +/- 1.42 micrograms/ml (C). Similarly, AUC0-infinity-values on day 1 with 16.9 +/- 4.8 (A), 20.2 +/- 6.7 (B) and 22.2 +/- 11.2 micrograms/ml x h (C) showed only modest (NS) differences between groups, but decreased markedly on day 4 to 10.8 +/- 1.8 (A), 13.6 +/- 5.8 (B) and 14.4 +/- 4.3 micrograms/ml x h (C). Linear regression analysis between AUC and C(Cr) demonstrated no relationship between these parameters. For plasma concentrations of M 1 no significant differences were seen between groups. At steady state maximal plasma concentrations of M 1 occurred earlier and were slightly increased. In one patient (group B) receiving tamoxifen comedication markedly elevated plasma concentrations of trapidil and desethyltrapidil occurred, suggesting a pharmacokinetic interaction. Trapidil may be safely given to patients with impaired renal function, the apparent decrease of trapidil plasma concentrations may suggest autoinduction of metabolizing enzymes.
Thürmann
P A
PA
Department of Clinical Pharmacology, University Hospital Frankfurt/Main, Germany.
Harder
S
S
Wolter
K
K
Münck
A C
AC
Fritschka
E
E
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007677:Kidney Function Tests; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D051437:Renal Insufficiency / Q000378:metabolism*; D013997:Time Factors; D014192:Trapidil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D010975:Platelet Aggregation Inhibitors; D010982:Platelet-Derived Growth Factor; D014192:Trapidil