Study On Absorption Behaviors Of S-propargyl-cysteine

S-propargyl-cysteine (SPRC) is a structural analog of S-allylcysteine (SAC) which is a sulfur-containing amino acid derived from garlic with antioxidant, anticancer, antihepatotoxic activities and cardioprotective effects. SPRC has cardioprotective effects in myocardial infarctions rats and could possibly be used to treat ischemic heart disease. Although the pharmacological effects of SPRC have been reported, the major physicochemical properties and absorption behaviors of SPRC have not been defined, which were the basis of developing SPRC oral dosage form.OBJECTIVEIn this study, we determined equilibrium solubility, pKa, logP and logD of SPRC, investigated its absorption behaviors in rat gastrointestinal tract via three dosages, different pH environment and different intestine segments, it's pharmacokinetics characteristic and bioavailability. All these study are important, necessary and valuable to design and development of oral dosage form and rational clinical usage of SPRC.METHODSaturation, electric titration and shake flask method were established to determine solubility, dissociation constant (pKa), true partition coefficient (logP) and apparent distribution coefficient (logD) of SPRC. Absorption mechanism of SPRC was investigated using rat in situ intestine perfusion model.An HPLC method was established for the determination of S-propargylcysteine (SPRC) in the intestinal recirculating perfusate. Phenlsulfonphthalein (PP) was determined simultaneously for volumn correction. A C18 column was used with the mobile phase of water-acetonitrile by gradient elution at the detection wavelengths of 220 and 362 nm.A simple, fast and sensitivemixed-mode reversed-phase and cation-exchange HPLC-MS/MS method has been developed and validated for the quantification of SPRC in the blood sample.RESULTThe equilibrium solubility of SPRC in water was 31.91±0.46mg·mL-1; pKa of SPRC on acidic and basic region were roughly estimated to be 2.93±0.13 and 7.73±0.33, respectively, isoelectric point (PI) was 5.33±0.23; logP of SPRC was-2.16±0.027. Rat in situ perfusion trial indicated that hourly absorption percentage (P%/h) of SPRC showed significant difference (P<0.05) in different pH perfusion solutions and in different intestine segment, however, hourly absorption percentage (P%/h) of SPRC showed no significant difference (P>0.05) in different concentration perfusion solutions. After oral administration, SPRC was rapidly absorbed and the maximum plasma concentration (Cmax) appeared at 1.1±0.5,1.3±0.5, and 2.5±1.8 h following 25,75, and 225mg/kg administration, respectively. Log transformed Cmax/Dose and AUCO-t/Dosewere not different between dose levels after a single i.g. or i.v. administration (P>0.05), and the mean Tmax were also found to be independent of dose (P>0.05), indicating a kinetic linearity. The absolute bioavailability of oral SPRC was calculated to be 96.6%,97.0%, and 94.7%, respectively.CONCLUSIONSPRC was categorized as biopharmaceutical classification system (BCS) class I drug, exhibited high solubility and permeability. Transport mechanism of SPRC was mainly membrane pore transport. Good absorption characteristic contribute to development of oral SPRC formulations.