Influence of renal failure on the kinetics of zimeldine and norzimelidine.
The kinetics of zimeldine (Z) and its demethylated metabolite, norzimelidine (NZ), were determined after administration of a single 200 mg oral dose of Z to 6 healthy volunteers (Group I), and to patients with mild (Group II) and severe renal failure (Group III). Z and NZ concentrations were assayed by HPLC in serial plasma and urine samples over 6 days following the dose. In Group I Z was rapidly absorbed and metabolized into NZ, and then the plasma concentrations declined with apparent elimination half-lives of 8.4 h and 24.9 h for Z and NZ respectively, whilst the renal clearance of both compounds was low, Z 15.7 ml/min and NZ 33.0 ml/min. The plasma level of Z differed little between Groups I and III, but the area under the curve was significantly higher in Group III than in Group I subjects (AUC0-144 = 17.3 and 6.8 mumol X l-1 X h, respectively). Severe renal failure did not affect the peak plasma concentration of NZ but it did significantly increase peak time, apparent elimination half-life, and the area under the plasma concentration curve. A significant inverse relationship was found between renal clearance of NZ and plasma creatinine. Since NZ is as pharmacologically potent as Z, the results suggest that the dose of Z should be reduced in patients with severe renal insufficiency.
Ferry
N
N
Cuisinaud
G
G
Cochat
P
P
Pozet
N
N
Zech
P Y
PY
Sassard
J
J
D000328:Adult; D000928:Antidepressive Agents / Q000378:metabolism*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D015031:Zimeldine / Q000031:analogs & derivatives* / Q000378:metabolism*
D000928:Antidepressive Agents; D015031:Zimeldine; C017578:norzimelidine