Pharmacokinetics of warfarin in the nephrotic syndrome and effect on vitamin K-dependent clotting factors.
The behavior of warfarin, a drug tightly bound to albumin, was studied in patients with nephrotic syndrome (NS) to assess the influence of hypoalbuminemia on its pharmacokinetics and its effect on vitamin K-dependent coagulation factors. A single dose of warfarin (8 mg) was given orally to 11 nephrotic patients with normal or nearly normal renal function and to 11 controls. In every subject the following measurements were performed: albuminemia before (t0) warfarin administration; plasma warfarin and vitamin K-dependent coagulation factors (FII, FVII, FIX, FX) levels, before and at time intervals from 0 to 48 h after drug administration; warfarin urinary excretion from 0 to 24 h. Urinary warfarin excretion was null in 19 out of the 22 subjects and very low in two nephrotic patients and in one control. Low serum albumin in NS patients induced a twofold increase of unbound warfarin vs controls (3.5% vs 1.8%, p less than 0.001) which led to a threefold increase in plasma clearance of warfarin (9.70 vs 3.26 ml X min-1, p less than 0.001); as warfarin distribution volume showed only a slight (non significant) increase in NS patients, the elimination half-life was thus markedly shortened in NS patients vs controls (18 vs 36 h, p less than 0.01). Maximum warfarin effect on vitamin K-dependent factor levels occurred at 18 h in controls and 24 h in nephrotics, and these lowest values were similar, in spite of a higher level at 0 in NS patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Ganeval
D
D
Fischer
A M
AM
Barre
J
J
Pertuiset
N
N
Dautzenberg
M D
MD
Jungers
P
P
Houin
G
G
D000293:Adolescent; D000328:Adult; D001779:Blood Coagulation Factors; D005164:Factor IX / Q000378:metabolism; D005167:Factor VII / Q000378:metabolism; D005170:Factor X / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009404:Nephrotic Syndrome / Q000378:metabolism* / Q000503:physiopathology; D011516:Prothrombin / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D014812:Vitamin K / Q000378:metabolism*; D014859:Warfarin / Q000378:metabolism* / Q000494:pharmacology
D001779:Blood Coagulation Factors; D012709:Serum Albumin; D014812:Vitamin K; D014859:Warfarin; D005167:Factor VII; D011516:Prothrombin; D005164:Factor IX; D005170:Factor X