High-performance liquid chromatographic assay of diltiazem and six of its metabolites in plasma: application to a pharmacokinetic study in healthy volunteers.
A sensitive and specific reversed-phase high-performance liquid chromatographic assay for simultaneous determination of plasma concentrations of diltiazem and six of its metabolites known to occur in humans is reported. Using 2 mL of plasma, the lower limit of quantitation of the assay was less than 10 ng/mL of diltiazem and each of the metabolites, with coefficients of variation of less than 10%. The assay was successfully applied to determine the kinetics of diltiazem and its major metabolites in four healthy volunteers after each received a single 90-mg oral dose of diltiazem. In addition to the previously reported two major metabolites in humans, deacetyl diltiazem (M1) and N-monodemethyl diltiazem (MA), another previously unreported major metabolite, deacetyl N-monodemethyl diltiazem (M2), was present at comparable concentrations to M1 and MA in all four volunteers. In addition, another metabolite, deacetyl diltiazem N-oxide (M1-NO), which was previously found most abundant in urine, was also estimated in the plasma of two volunteers. Two other known human metabolites, deacetyl O-demethyl diltiazem (M4) and deacetyl N,O-didimethyl diltiazem (M6), were not detected in any of the four study subjects. The average maximum plasma concentrations of M1, M2, MA, and M1-NO were 10, 15, 26, and 13%, respectively, of the mean maximum diltiazem concentrations.
College of Pharmacy, Department of Medicine, Dalhousie University, Nova Scotia, Canada.
P K
PK
Yeung
T J
TJ
Montague
B
B
Tsui
C
C
McGregor
D000284:Administration, Oral; D000328:Adult; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004110:Diltiazem / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male
D004110:Diltiazem