The metabolic fate of Sormodren (bornaprine hydrochloride) in animals and humans

Abstract

1. Single oral doses of the anticholinergic drug [¹⁴C]Sormodren to rats (1 mg/kg), dogs (0.3 mg/kg) and humans (0.03 mg/kg) were well absorbed. Excreted in urine and faeces were means of 31 and 70%, 53 and 39%, and 78 and 4% in rats, dogs, and humans, respectively, during five days: excretion was prolonged and still incomplete at five days in humans.

2. Peak plasma levels of ¹⁴C (scaled for dose) were generally reached within 1–2h after oral doses in rats, 49 (ng/ml)/(mg/kg), dogs 290 (ng/ml)/(mg/kg) and humans 410(ng/ml)/(mg/kg), and declined with half-lives of approx. 5, 12 and 30 h, in these species respectively. Repeated oral doses of [¹⁴C]Sormodren to dogs resulted in some accumulation of ¹⁴C in the plasma.

3. Tissue concn. of ¹⁴C in dogs were generally higher than those in rats, particularly in the brain, lungs and eyes. The tissue distribution of ¹⁴C in rats and dogs was consistent with that of a compound readily eliminated by both renal and hepatic routes.

4. Basic metabolites in dog and human, urine and plasma were investigated using a combination of h.p.l.c. and g.l.c.-mass spectrometry. Unchanged Sormodren was not detected in the dog samples and was only a minor component in human urine and plasma. Some metabolites were present as conjugates.

5. A basic extract of enzyme-hydrolysed dog urine (5 mg/kg dose) contained 42% of the urine ¹⁴C. The major metabolites in this fraction were identified as three isomers of monohydroxy-N-desethyl-Sormodren and three isomers of monohydroxy-Sormodren, resulting from hydroxylation in the bicyclic ring. The positions of oxidation were not determined. A similar extract from dog urine (0.3 mg/kg dose) contained 26% of the urine ¹⁴C and the major metabolites were identified as isomers of monohydroxy-N-desethyl-Sormodren.

6. A basic extract of enzyme-hydrolysed human urine (0.03 mg/kg dose) contained 23% of the urine ¹⁴C. The unchanged drug was only a minor component and most of the radioactivity was associated with five isomers of monohydroxy-Sormodren, hydroxylation having occurred in the bicyclic ring.

7. Basic extracts of dog and human plasma only contained about 10% of the plasma ¹⁴C. Metabolites were chromatographically similar to the hydroxylated metabolites identified in the corresponding urine samples.