Metabolism and excretion of the quaternary ammonium compound thiazinamium methylsulfate (Multergan) in man. II. Oral and rectal administration.

Abstract

In this study it is shown that biotransformation of thiazinamium, when given orally, does not differ qualitatively from the pattern found after parenteral administration. However, quantitatively both the metabolism and excretion patterns are considerably different from those after intravenous injection. The renal clearance accounted for 256 +/- 136 ml.min-1 (mean +/- SD). This value is higher than glomerular filtration, which may be indicative of an active excretion process. Hepatic clearance (biotransformation and biliary excretion of unchanged cation) was 537 +/- 495 ml.min-1 (mean +/- SD). Hepatic clearance was found to correlate negatively with bioavailability. The ratio between unchanged drug and the only metabolite, the sulfoxide, in urine was about I:0.9. This is substantially different from that found after parenteral administration (ca. I:0.2), which may imply that a 'first-pass effect' occurs. It was estimated that ca. 50% of the absorbed amount was metabolized during the first liver passage. The fate of thiazinamium after rectal administration in Witepsol HI5 suppositories shows several similarities with that after oral administration. The ratio between unchanged drug and metabolite in urine in this case was ca. I:0.8, indicating that also after rectal administration a 'first-pass effect' occurs, now to a degree of ca. 35%.