Stereoselective disposition and metabolism of disopyramide in pediatric patients.
Pharmacokinetics of disopyramide (DP) enantiomers was studied in six pediatric patients, 5 to 12 years old, with arrhythmias after i.v. and p.o. administrations of racemic DP. The enantiomers of DP and its active metabolite, mono-N-dealkyldisopyramide, in plasma and urine were determined using a chiral, high-performance liquid chromatography. Plasma protein binding of DP was measured by ultrafiltration. Because the protein binding of DP was not only concentration-dependent but also stereoselective (i.e., S-DP binds to protein more extensively than R-DP), unbound pharmacokinetic parameters were used for evaluating the kinetic behaviors of DP enantiomers. The pediatric age patients had the mean (+/- S.D.) systemic clearance of 15.0 +/- 3.8 and 12.7 +/- 3.9 ml/min/kg for unbound S- and R-DP, respectively, which were not only stereoselectively different (P less than .05) but also at least about twice greater than the reported normal adult values. The mean postinfusion elimination half-life values for unbound S- and R-DP (2.7 +/- 0.5 and 2.8 +/- 0.4 hr, respectively) in pediatric patients were shorter than those reported from normal adults (approximately equal to 4 to 5 hr). The mean nonrenal (i.e., hepatic) clearance for unbound S- and R-DP (11.1 +/- 4.1 and 8.1 +/- 3.9 ml/min/kg, respectively) were also stereoselectively different (P less than .01) and accounted for approximately equal to 70% of the unbound systemic clearance of the respective enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)
Echizen
H
H
Division of Geriatric Health and Nutrition, National Institute of Health and Nutrition, Tokyo, Japan.
Takahashi
H
H
Nakamura
H
H
Ochiai
K
K
Chiba
K
K
Koike
K
K
Ogata
H
H
Ishizaki
T
T
D000284:Administration, Oral; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004206:Disopyramide / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010276:Parasympatholytics / Q000097:blood; D011485:Protein Binding; D013237:Stereoisomerism
D001798:Blood Proteins; D010276:Parasympatholytics; C030438:4-(isopropylamino)-2-(2-pyridyl)-2-phenylbutyramide; D004206:Disopyramide