Metabolic fate of a new histam ine H2-receptor antagonist, Z-300, in rat

Abstract

1. The metabolisms of (N-[3-[3-(piperidinomethyl)-phenoxy]-propyl]-2-(2-hydroxyethyl-1-thio) acetamide 2-(4-hydroxy benzoyl) benzoate) (Z-300) in rat have been studied. 2. Five metabolites were identified, namely as sulphoxide (SO), sulphone (SO2), phenol (PH), propionic acid (PA) and thioglycolic acid (TH) derivatives. Furthermore, two metabolites, M1 and M2, were proposed as PH conjugated to sulphate and glucuronic acid respectively. 3. There were several metabolites in the plasma samples after oral administration of 14C-Z-300. The main metabolites were PH (mainly existing as the conjugates), PA and SO, and Z-300 was present as <10% of plasma radioactivity. SO2 and TH were barely detected in plasma. In the urine, the composition of metabolites was similar to that in the plasma. In the bile, the main metabolites were PH (mainly existing as the conjugates) and SO, and very little Z-300 was detected. In the faeces, the main compounds were Z-300 and TH, and very little SO. 4. During in vitro metabolism experiments, Z-300 was metabolized mainly in the liver, and a little in the kidney and lung. PH or its conjugates were produced little on the in vitro metabolism; this was different from that found in the in vivo experiment. The metabolism of Z-300 to SO appeared to be catalysed by cytochrome P450 rather than the flavin-containing monooxygenase. Both hepatic clearance calculated from the in vitro metabolism experiment (28.9 ml/min/kg) and from the liver perfusion metabolism experiment (33.2 m/min/kg) were lower than the total clearance from the in vivo experiment (119 ml/min/kg). 5. After administration of 14C-SO into the caecum of rat, SO was converted to Z-300 and excreted in the faeces. 14C-SO was reduced by incubation for 4 h within the caecal content of rat under an anaerobic condition in vitro. The results suggest that SO was reduced to Z-300 by gut flora in the lower intestine.