The pharmacokinetics of a new 5-hydroxytryptamine (5HT,) receptor antagonist, 4-amino-5-chloro-2-[(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl]benzamide (ML-1035, l ) , and its sulfone and sulfide metabotiies were examined in 12 rats. Each of these compounds (25.4 fimol/kg) was administered to rats intravenously. Their plasma concentrations were measured by high-performance liquid chromatography. These plasma data revealed that 1, a sulfoxide, underwent interconversion with its sulfide metabolite. However, no interconversion was observed between 1 and its sulfone metabolite. Examination of mean times and additional properties of the l/sulfide metabolite system revealed that total exposure times of 1 and the sulfide metabolite were moderately and weakly, respectively, influenced by the metabolic interconversion process. However, the tissue distribution process strongly influenced the total exposure times of both compounds. The disposition of the sutfone metabolite of 1 was also strongly influenced by the tissue distribution process. In addition, ~3 % of the intravenous dose of 1 or the sulfide was available to the general circulation as the sulfone metabolite.
4-Amino
-5-chloro-2-[ (methylsulfinyl)ethoxy]-N-[ 2-(diethy-1amino)ethyllbenzamide (ML-1035,l; Scheme I) is a sulfoxide and a new selective gastroprokinetic agent. It is an analogue of metoclopramide, which has been in wide clinical use as an \ t C~CH,-S-CH, \ CH,-CH,-S-CHl 2 ' 1 0 3 Scheme I-Chemical structures and reaction scheme of 1 and its sulfide
(2) and sulfone (3) metabolites: CL,, is the conversion clearance of 1 to 2; Cb, is the conversion clearance of 2 to 1; CL,, is the sum of all elimination processes operating on 1 except CL12; CL,, is the sum of all elimination processes operating on 2 except C h , ; and CL,, is the formation clearance of 3.