GASTRIC PH INFLUENCES THE APPEARANCE OF DOUBLE PEAKS IN THE PLASMA CONCENTRATION-TIME PROFILES OF CIMETIDINE AFTER ORAL-ADMINISTRATION IN DOGS

被引：31

作者：

MUMMANENI, V ^{[1
]}

AMIDON, GL ^{[1
]}

DRESSMAN, JB ^{[1
]}

机构：

[1] UNIV MICHIGAN, COLL PHARM, ANN ARBOR, MI 48109 USA

来源：

PHARMACEUTICAL RESEARCH | 1995年 / 12卷 / 05期

关键词：

CIMETIDINE; DOUBLE PEAKS; BIOAVAILABILITY; ABSORPTION RATE CONSTANT; GASTRIC PH; INTESTINAL PH; GASTRIC EMPTYING;

D O I：

10.1023/A:1016284214708

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The plasma concentration-time profiles of cimetidine often exhibit two peaks following oral administration of a single dose in the fasted state, while the concurrent administration of some antacids results in a lower extent as well as rate of absorption. In the present work, absorption of cimetidine after a single dose in the fasted state was studied as a function of gastric pH in male beagle dogs to determine whether gastric pH plays a role in the double peak phenomenon and/or can account for the decrease in bioavailability when antacids are coadministered. The extent of absorption of cimetidine was not influenced significantly by gastric pH, indicating that elevation of gastric pH is not the cause of decreases in the bioavailability of cimietidine when it is administered with antacids. Distinct double peaks or plateaux were noted in 8 of 10 plasma profiles when the gastric pH was 3 or below. Irregular absorption behavior was observed in 2 of 6 profiles in the pH range of 3 to 5, while single peaks were observed in all 10 profiles when the gastric pH was maintained at pH greater than or equal to 5. It was concluded that gastric pH is a major factor in the generation of cimetidine double peaks. Changes in gastric pH also resulted in changes in the apparent kinetics of absorption. Below pH 5, absorption mostly followed zero-order kinetics (9 of 16 profiles) or a more complex kinetic process involving at least two components to the absorption phase (5 of 16 profiles). At gastric pH greater than or equal to 5, however, absorption followed first order kinetics in 7 of 10 profiles. These differences in kinetics of absorption are postulated to arise from variations in gastric emptying as a function of pH and/or carryover effects of gastric pH into the upper intestine.

引用

页码：780 / 786

页数：7

共 28 条

[1]

Bodemar G., Norlander B., Fransson L., Walan A., The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidine—studies in patients with peptic ulcer disease, Br. J. Clin Pharmac., 7, pp. 23-31, (1979)

[2]

Clements J.A., Heading R.C., Nimmo W.S., Prescott. L.F., Kinetics of acetaminophen absorption and gastric emptying in man, Clin. Pharmacokin., 24, pp. 420-431, (1978)

[3]

Lui C.Y., Oberle R., Fleisher D., Amidon G.L., A radiotelemetric method for evaluation of enteric coating performance: comparison of enteric coated and plain aspirin tablets, J. Pharm. Sci., 75, pp. 469-474, (1986)

[4]

Hammerlund M.M., Palzow L.K., Odlind B., Pharmacokinetics of furosemide in man after intravenous and oral administration, Eur. J. Clin. Pharmacol., 26, pp. 197-207, (1984)

[5]

Bergstrom R.F., Kay D.R., Harkeson T.M., Wagner. J.G., Penicillamine kinetics in normal subjects, Clin. Pharmacol. Therap., 30, pp. 404-413, (1981)

[6]

Dressman J.B., Berardi R.R., Elta G.H., Gray T.M., Montgomery P.A., Lau H.S., Pekeloudas K.L., Szpunar G.J., Wagner J.G., Absorption of flurbiprofen in the fed and fasted states, Pharm. Res., 9, pp. 901-907, (1992)

[7]

Gugler R., Brand M., Somogyi A., Impaired cimetidine absorption due to antacids and metoclopramide, Eur. J. Clin. Pharmacol., 20, pp. 225-228, (1981)

[8]

Steinberg W.M., Lewis J.H., Katz D.M., Antacids inhibit absorption of cimetidine, New Eng. J. Med., 307, pp. 400-404, (1982)

[9]

Dressman J.B., Yamada K., Animal models for oral drug absorption, Pharmaceutical Bioequivalence, (1991)

[10]

Youngberg C.A., Wlodyga J., Schmaltz S., Dressman. J.B., Radiotelemetric determination of gastrointestinal pH in four healthy beagles, Am. J. Vet. Res., 46, pp. 1516-1521, (1985)

← 1 2 3 →