EFFECT OF N-METHYLGLUCAMINE SALICYLATE ON THE GASTROINTESTINAL ABSORBTION OF ALPHA-METHYLDOPA IN RATS

SAMI S ZOGHBI, Purdue University

Abstract

N-Methylglucamine, 1-deoxy-1-(methylamine)-D-glucitol, is a solubilizing and stabilizing agent in pharmaceutical preparations. Through the formation of N-methylglucamine salts, several drugs, which were otherwise not water soluble, become soluble and readily absorbed from the gastrointestinal tract. Pharmacokinetic studies in man and animals have shown that N-methylglucamine salicylate has acquired therapeutic blood salicylate levels with considerable less gastrointestinal damage than acetylsalicylate. The compound was suggested for use in conditions requiring systemic salicylate therapy. (alpha)-Methyldopa, 3-(3,4-dihydroxyphenyl)-2-methyl-L-alanine, is a highly effective antihypertensive agent. Pharmacologic studies in man and rats have shown that about 15-50% of the orally administered dose was absorbed from the gastrointestinal tract. For effectiveness of the drug and without causing any adverse side effects, patients that are being treated with (alpha)-methyldopa usually undergo individual adjustment of dosage. N-Methylglucamine salicylate is completely ionized when in aqueous media. If this drug were administered with a compound such as (alpha)-methyldopa, the possibility of N-methylglucamine influencing the absorption of (alpha)-methyldopa is probable. This research involved the in vivo study of the blood and plasma levels of (alpha)-methyldopa when (alpha)-methyldopa was administered orally with and without N-methylglucamine salicylate. Preliminary experiments were conducted utilizing ('3)H-(alpha)-methyldopa. The radiochemical purity was determined using thin layer chromatography in conjunction with liquid scintillation techniques. ('3)H-(alpha)-methyldopa was shown to be at least 96% radiochemically pure. ('3)H-(alpha)-methyldopa was administered orally, to fasted rats, with and without N-methylglucamine. Periodical blood withdrawal from cannulated rats, made it feasible to monitor the blood radioactivity levels. Blood levels of radioactivity in the rats showed that they differed, indicating that there was interference between N-methylglucamine and (alpha)-methyldopa. However variability within treatment groups was high, probably due to variability in the rate of metabolism of (alpha)-methyldopa. Consequently, the measurement of radioactivity in the blood was not considered a good indication of (alpha)-methyldopa absorption. Fluorometric assays, specific for (alpha)-methyldopa, were done on plasma samples obtained from three groups of rats. Plasma samples were collected from rats by decapitation and exsanguination. Each of the three groups of rats received orally either (alpha)-methyldopa, (alpha)-methyldopa with N-methyl-glucamine salicylate simultaneously, or (alpha)-methyldopa 2 hours after N-methylglucamine salicylate. Results showed that N-methylglucamine salicylate decreased the gastrointestinal absorption of (alpha)-methyldopa when the two were given simultaneously, but there was no interference when the two doses of (alpha)-methyldopa and N-methylglucamine salicylate were staggered.

Degree

Ph.D.

Subject Area

Pharmacology

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