Pharmacokinetics and Excretion of the Novel Anti-tuberculosis Compound 1,2:5,6-Di-O-isopropylidene-3-O-(phenyl cyclopropyl methanonyl)-α-D-glucofuranose (S-001-14) after Oral Doses in Rats

Abstract

A sensitive and reproducible high performance liquid chromatography (HPLC)-UV method for the determination of the novel anti-tuberculosis compound l,2:5,6-di-o-isopropylidene-3-O-(phenyl cyclopropyl methanonyl)-α-D-glucofuranose (S-001-14) has been developed and validated in rat serum, urine and feces. Following extraction with hexane at alkaline pH, samples were separated on a reverse phase C18 column and quantified using UV detection at 267 nm. The mobile phase was 70% acetonitrile in ammonium acetate buffer (10 mmol/L, pH 6.0) with a flow rate of 1.0 ml/min. The method was used to determine the pharmacokinetics and excretion of S-001-14 after oral doses in rats. Linearity was satisfactory over the concentration range of 5 – 500 ng/ml (r², >0.99). Recoveries were >90% and were consistent throughout the calibration range. The precision and accuracy were acceptable as indicated by relative standard deviation ranging from 2.72 to 9.54%, bias values ranging from 1.62 to 12.05%. Moreover, S-001-14 was stable in rat serum after being subjected to three freeze-thaw cycles and for 30 days on storage at −60 °C. The method was used to determine the serum concentration-time profiles for S-001-14 after oral doses of 4,100 and 200 mg/kg in rats. A linear pharmacokinetics was found in rats at 100 and 200 mg/kg doses with a long elimination half-life (~24 h), wide distribution and bioavailability of ~13%. The excretion study after the 100 mg/kg oral dose revealed that S-001-14 was excreted in urine (0.002 ± 0.001%) and feces (15.6 ± 3.5%).

Key words

Anti-tuberculosis agents - Phenyl cyclopropyl methanones - S-001-14, HPLC, pharmacokinetics, rat

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