Pharmacokinetics of Compound 58–112, a Potential Skeletal Muscle Relaxant, in Man

Abstract

The pharmacokinetics of 4‐[(3‐methoxyphenyl)methyl]‐2,2,6,6‐tetramethyl‐1‐oxa‐4‐aza‐2,6‐disilacyclohexane (Sandoz compound 58–112), a new chemical entity with a unique myotonolytic effect, was studied in 12 healthy male volunteers who received an oral dose of 50 or 100 mg of the ¹⁴C‐labeled drug. Serial blood and breath samples and complete urine and feces were collected for 120 hours after dosing. All samples were analyzed for total radioactivity while the blood and urine were also assayed for unchanged compound 58–112. Measurable blood radioactivity levels were observed at 0.5 hour, and peak concentrations were attained at 1 to 2 hours after dosing. The absorption of the radioactive doses was complete and appeared linear in the 50–100 mg range, as indicated by blood ¹⁴C levels that were proportional to the dose. The 50‐ and 100‐mg doses also resulted in virtually identical excretion patterns, with 95 per cent of the administered radioactivity recovered within 9 hours, almost exclusively in the urine. However, the disproportionately higher blood concentrations of unchanged compound 58–112 after the 100‐mg dose could suggest saturable presystemic metabolism in the liver. Simultaneous fitting of all data in the 100‐mg dose study to a pharmacokinetic model showed that unchanged compound 58–112 was distributed into a central and a peripheral compartment and was eliminated entirely by metabolism, the distribution and elimination half‐lives being 0.5 and 3.9 hours, respectively. The metabolite(s) was distributed into one homogeneous space, and its elimination half‐life was 0.1 hour, with a renal:fecal clearance ratio of ∼96:4.