Metabolism of xilobam in laboratory animals and man

Abstract

1. Biotransformation and excretion of xilobam (Xm) were studied after single oral doses of Xm-¹⁴C in mouse, rat, dog and man.

2. Following oral administration of Xm-¹⁴C, recoveries of total ¹⁴C (0–24 h) in urine were ± 78% of the dose in all species.

3. Xm and a total of 11 metabolites have been isolated and identified, which accounted for 30, 65, 21 and 49% of the total ¹⁴C in the urine samples from mouse, rat, dog and man, respectively.

4. Xm was sequentially oxidized at the pyrrolidine ring to form 5′-OH Xm and 5′-oxo Xm. Both metabolites were isolated from human plasma accounting for 61% of the radioactivity in the sample. 5′-OH Xm was also identified as a major in vitro metabolite in the 9000g supernatant from a rat liver homogenate preparation.

5. 5′-OH Xm was isolated from the urine of all species except rats. However, oxidation products of 5′-oxo Xm were also present. Oxidation at the phenyl (ph) ring and at the phCH₃ group produced the corresponding 4-OHph and phCH₂OH metabolites. Subsequent water addition at the 2-position of the pyrrolidine ring followed by cleavage and/or cyclization of the above metabolites resulted in six additional urinary metabolites.