Evaluation of pharmacokinetics, bioavailability and dose linearity of diltiazem in healthy volunteers.
The objective of this randomized five-way cross-over study with healthy male volunteers was to determine, one the one hand, the bioavailability and main pharmacokinetic parameters of 4 sustained release diltiazem (Surecaps, CAS 42399-41-7) test preparations with ascending doses (180, 240, 300, 360 mg), administered as single application, versus an immediate release 60 mg diltiazem reference preparation, which was given thrice a day at 8-h intervals. On the other hand, the study also allowed the evaluation of a possible dose linearity of the test substance diltiazem. Plasma concentrations of diltiazem and its major metabolite desacetyl-diltiazem were measured by high pressure liquid chromatography (HPLC) up to 48 h after single dosing of the sustained release preparations as well as after repeated doses of the immediate release formulation. The undesired side effects/concomitant symptoms observed are known to occur after diltiazem administration. For the area under the curve, e.g. calculated from time 0 to the last quantifiable sample (AUC0-Tlast), the study revealed for the parent compound diltiazem mean values of 926.2, 1602.4, 1873.2 and 2415.7 h.ng/ml after administration of the 4 sustained release test preparations, respectively; for the immediate release reference preparation the value was 1007.2 h.ng/ml. Concerning the main metabolite desacetyl-diltiazem the corresponding values for the 4 sustained release formulations were 138.6, 236.9, 280.2 and 345.6 h.ng/ml, respectively. The corresponding value for the immediately release formulation was 127.5 h.ng/ml. Concerning a possible dose linearity of diltiazem, statistical analysis revealed a convincing linear relationship between at least 3 of the 4 sustained release preparations, therefore linearity may be assumed between 240 and 360 mg.(ABSTRACT TRUNCATED AT 250 WORDS)
Hutt
V
V
L.A.B. Gesellschaft für Pharmakologische Untersuchungen mbH & Co., Neu-Ulm, Fed. Rep. of Germany.
Janik
F
F
Kappler
J
J
Pabst
G
G
Ravelli
V
V
Maccari
M
M
Jaeger
H
H
D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004110:Diltiazem / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013056:Spectrophotometry, Ultraviolet
C037769:deacetyldiltiazem; D004110:Diltiazem