Metabolism and disposition of (RS)-2-methoxy-3-(octadecylcarbamoyloxy)propyl 2-(3-thiazolio)ethyl phosphate (MOTP) in rats and dogs

Abstract

1. Metabolites (RS)-4-[(3-hydroxy-2-methoxy)propoxycarbonylamino]butanoic acid (I) and (RS)-2-[(3-hydroxy-2-methoxy)propoxycarbonylamino]acetic acid(II) were isolated from urine after i.v. administration of (RS)-2-methoxy-3-(octadecyl-[¹⁴C]carbamoyloxy)propyl 2-(3-thiazolio)ethyl phosphate (¹⁴C-MOTP) to rats and characterized by t.l.c., g.l.c.-mass spectrometry and p.m.r. spectrometry.

2. After i.v. administration of ¹⁴C-MOTP, the plasma concentration of the drug declined biphasically with half-lives of 0·22 and 3·94 h in rats, and 0·81 and 8·00 h in dogs. In rats and dogs, unchanged MOTP was the main ¹⁴C component in the plasma, together with a small amount of I and II. ¹⁴C-MOTP was highly bound to plasma protein of both animals.

3. Five min after i.v. administration of ¹⁴C-MOTP to rats, ¹⁴C was widely distributed in tissues, with the highest conc. in the lung and the lowest in the eye. The distribution of ¹⁴C was relatively slow in some tissues. In most tissues, ¹⁴C decreased to low levels at 96 h, except in the Harder's gland.

4. Elimination of ¹⁴C-MOTP was almost complete within 120h in rats and 144h in dogs. In both species, the administered ¹⁴C was excreted largely in the urine as I and II, with the remainder appearing in the faeces and the expired air. Biliary excretion and reabsorption of ¹⁴C were detected in rats.

5. During repeated i.v. administration of ¹⁴C-MOTP to rats for 7 days, the conc. of ¹⁴C in plasma and most tissues attained steady state within 5 days, except in Harder's gland, where the level rose gradually until the seventh day of dosing. Within 6 days after the last dosing, 96% of the injected dose was eliminated from the body.