Abstract4-Amino-5-chloro-substituted benzamides have been shown to increase gastric motility in-vivo and enhance field-stimulated and peristaltic contractions in-vitro. The present experiments examined the contractile response to a series of benzamides in the guinea-pig non-stimulated ileum. Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 μm acetylcholine (% acetylcholine response = 12 ± 2, 19 ± 3, 26 ± 2, 51 ± 3, n= 13, 8, 17, and 21, with EC50 values of 0·85, 1·8, 5·7, and 14·2 μm for cisapride, zacopride, metocloprarmde, and ML-1035 (4-amino-5-chloro-2-((2-methylsulphinyl)-ethoxy)-N-(2-(diethylamino)-ethyl)-benzamide hydrochloride), respectively). ML-1035 contractions were completely blocked by atropine and tetrodotoxin, while ganglionic blockade with hexamethonium was ineffective. Metoclopramide has been reported to sensitize postjunctional muscarinic receptors, however, ML-1035 did not enhance acetylcholine-induced contractions. Tropisetron (ICS 205–930, 1 μm), caused a parallel rightward shift in the concentration-response curve for both ML-1035 and zacopride (EC50 = 14·2 ± 1·3 and 1·8 ± 0·8 μm in the absence, and 26 ± 2·7 and 6·9 ± 2·3 μm in the presence of tropisetron for ML-1035 and zacopride, respectively) with apparent pKB values of 5·9 and 6·0 for the respective compounds. 5-Hydroxytryptaminergic receptor desensitization by 2-methyl-5-hydroxytryptamine (5-HT3) and 5-methoxytryptamine (5-HT4), attenuated the response to ML-1035. We also examined the effect of the benzamides on [3H]acetylcholine release from longitudinal muscle myenteric plexus preparations; however, these compounds had little effect on basal [3H]acetylcholine release. Thus, the pharmacological data indicate that the benzamides can elicit neurogenic contractions in the non-stimulated ileum by activating postganglionic, cholinergic neurons which is independent of an effect on smooth muscle.

01 Mar 1994·Journal of Pharmaceutical SciencesQ3 · MEDICINE

Determination of Bioavailability and Systemically Available Fractions of Drugs Undergoing Reversible Metabolism: Application to 4-Amino-5-chloro-2-[2- (methylsulfinyl)ethoxy]-/V-[2-(diethylamino)ethyl]benzamide and Its Sulfide and Sulfone Metabolites in Rats

Q3 · MEDICINE

Article

Author: Be-Sheng Kuo ; James C. Poole ; Kin-Kai Hwang ; Haiyung Cheng

Methods are discussed which permit the calculation of the bioavailability (F) and fraction of an oral dose entering the central circulation (f) of a drug and its interconversion metabolite. The interrelationships between the F and f and between the F and systemically available fractions afforded by reversible metabolism are also derived and described. The application of these principles is illustrated by the pharmacokinetic analysis of 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2- (diethylamino)ethyl]benzamide (ML-1035, 1) and its sulfide (2) and sulfone (3) metabolites in rats. Like intravenous ML-1035, ML-1035 administered orally underwent metabolic interconversion with 2 but not with 3 in this species. Both ML-1035 and 2 were absorbed rapidly and are pharmacologically active. On average, 8.3 and 13% of an oral dose (152.4 mumol/kg) of ML-1035 were bioavailable as ML-1035 and its sulfide metabolite, respectively, while 23 and 65% of a molar equivalent dose of the sulfide metabolite were bioavailable as either compound, respectively. Thus, the sulfide metabolite is better absorbed than ML-1035 in rats. Following oral administration of either ML-1035 or 2, the systemically available fractions of both compounds were weakly to moderately influenced by the reversible metabolism process in rats. Moreover, the bioavailability of the sulfone metabolite was very poor (2.5-4%) following separate oral administration of ML-1035, 2, and 3.

01 Jan 1992·Pharmaceutical ResearchQ3 · MEDICINE

Validation of a column-switching high-performance liquid chromatographic (HPLC) method for determination of ML-1035 and its five metabolites in plasma.

Q3 · MEDICINE

Article

Author: Be-Sheng Kuo ; James C. Poole ; Kin-Kai Hwang

A fully automated column-switching HPLC procedure has been developed and validated for quantitation of ML-1035 and its five metabolites in plasma employing direct injection. Plasma samples were injected onto a CN extraction column (4 x 4.6 mm, 5 microns) for micellar cleanup with 0.5% sodium dodecyl sulfate (SDS) in 50 mM phosphate. The proteinaceous components were solubilized and flushed out. The extracted compounds were then eluted by forward flush onto a C8 analytical column (150 x 4.6 mm, 5 microns) for further analysis using fluorescence detection (excitation, 308 nm; emission, 350 nm). After the subsequent washing and reequilibration with a sequence of three solvent mixtures, the extraction column was ready for the next injection. The limit of quantitation for all compounds of interest was about 10 to 15 ng/ml using 100 microliters of plasma. Excellent precision, accuracy, and linearity were obtained for all compounds over a range of 10 to 1500 ng/ml. The practicality of the HPLC method was also validated with plasma samples from dogs receiving ML-1035. Longevity for both extraction and analytical columns is excellent. Micellar cleanup coupled with the column-switching technique is a promising HPLC procedure when using direct injection of biological fluids.

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