Intragastric behavior and absorption kinetics of a normal and "floating" modified-release capsule of isradipine under fasted and fed conditions.
From measurements of drug levels in both gastric juice and plasma, we investigated whether or not a prolonged gastric residence time (GRT) is responsible for the slow absorption kinetics of a "floating" modified-release (MR) capsule of isradipine [isopropyl methyl (+/-)-4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5- pyridinedicarboxylate], a lipophilic dihydropyridine calcium channel blocker. The effects of a "high-fat" breakfast on the intragastric behavior and absorption kinetics were also assessed. In an open crossover design, five healthy subjects ingested either a normal or MR capsule of isradipine under fasted conditions. Serial samples of gastric juice (obtained via an indwelling nasogastric tube) and plasma were collected up to 24 h after drug intake, and were analyzed for isradipine by GC and RIA methods, respectively. The pH and titratable acid, protein, and pepsin concentrations of the gastric juice samples were also determined. Four additional subjects were similarly studied after ingesting the capsules following a high-fat breakfast. Under fasted conditions, gastric juice drug levels of the normal and MR capsules indicated a median GRT of less than 1.5 h in both cases. Plasma levels indicated a rapid absorption for the normal capsule (less than 2 h), but a remarkably slow absorption for the MR capsule, lasting 24 h or more. Under fed conditions, gastric juice and plasma profiles of the normal capsule were similar to those for the fasted case. In contrast, the MR capsule had an increased GRT (approximately 2.4 to 4.8 h) that was associated with a delayed and more extensive intragastric drug release. The corresponding plasma profiles showed a rapid absorption phase which correlated closely with the intragastric release kinetics. The influence of a high-fat meal on the release kinetics of the MR capsule did not appear related to the intragastric pH, or acid, protein, or pepsin concentrations. From these results we conclude that: (1) a prolonged GRT is not responsible for the slow absorption achieved with a "floating" MR capsule; (2) the presence or absence of food, rather than buoyancy, is the principal determinant of the GRT of the MR capsule; (3) the release and absorption of a lipophilic drug from a "floating" MR capsule may be affected by intragastric interaction with the lipid phase of meal; and (4) the major portion of drug release from the MR capsule takes place in the colon, rather than in the stomach.
Mazer
N
N
Department of Product Development, Sandoz, Ltd., Basle, Switzerland.
Abisch
E
E
Gfeller
J C
JC
Laplanche
R
R
Bauerfeind
P
P
Cucala
M
M
Lukachich
M
M
Blum
A
A
D000328:Adult; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002214:Capsules; D003692:Delayed-Action Preparations; D005215:Fasting; D005260:Female; D005502:Food; D005750:Gastric Juice / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D017275:Isradipine; D008297:Male; D008954:Models, Biological; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012995:Solubility
D002121:Calcium Channel Blockers; D002214:Capsules; D003692:Delayed-Action Preparations; D011725:Pyridines; D017275:Isradipine