| FY-10, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthyl) propenyl]-benzoic acid,2-amino-2-(hydroxymethyl)-1,3-propanediol, is a new agent, which contains an active arotinoid moiety linked to 2-amino-2-(hydroxymethyl)-1,3-propanediol. It is the active arotinoid moiety (TTNPB) in a body that exihibits anti-psoriasis. In the present, FY-10 was under the phase of preclinical study. Until now, there are few reports on the pharmacokinetic study on arotinoid because of its lability and the lower dosage used in the preclinical.Levodropropizine, (S(-)-3-(4-phenyl-1-piperazinyl)-1,2-propanediol), the (-)-enantiomer of dropropizine, was used as an antitussive drug in clinical on the central nervous system, which exhibits an antitussive activity comparable to dropropizine, with a reduced sedative effect and seems to be attributable to the (+)-enantiomer. The methods used for the determination of levodropropizine suffered form either a higher LLOQ or a time-consuming or labor-intensive sample preparation.1. Pharmacokinetics study on FY-10 in animals. The objective of this study was to establish an accurate and simple method in order to estimate the pharmacokinetics of FY-10 in animals (mice, dogs and rats). The results were shown as below:After FY-10 was administered to mice at a single dose of 4, 16 and 64μg·kg-1, respectively, by gastrogavages, the main pharmacokinetic parameters were fitted with one-compartment model and not varied with the increase of dose, therefore, linear pharmacokinetic characteristics were found. Sex differences were found in arotinoid pharmacokinetics in mice, dogs and rats. Longer half-life (18, 44 and 32 h for mouse, dog and rat, separately.) was found which indicated that FY-10 was cleared slowly in animals. The absolute bioavailability of FY-10 was more than 91% when FY-10 granules formulation was used.2. Tissue distribution study on FY-10 in mice. A sensitive and selective LC/MS/MS method was developed for the quantification of arotinoid in mice tissues. FY-10 was distributed to tissues extensively in mice after an oral administration of 16.0μg·kg-1 FY-10. The concentration of FY-10 was high in ovary, gastro-wall, thighbone, adrenal gland, lung, liver and fat. The concentrations of FY-10 in tissues at 24 h post-dose except for skin, heart, fat, eyeball, brain and lung were lower than 15% of that at 0.5 h post-dose. And the concentrations of FY-10 in tissues after treated with 16.0μg·kg-1 FY-10 once daily for 7 days were similar with those treated with 16.0μg·kg-1 FY-10 only once except in fat, which meant FY-10 was not accumulated in these tissues except in fat.The plasma protein binding ratio was tested and a higher plasma binding ratio (>97%) was found, which was similar with other retinoids.3. Metabolism and excretion studies on FY-10 in rats. An oral administration by gastrogavages of 11.2μg·kg-1 FY-10 was given to rats in order to estimate the excretion of FY-10 in rats. FY-10 was lessly excreted from urine and the cumulative amount within 96 h reached to 0.14% of the dose whereas the unchanged cumulative amount in feces within 120 h reached to 7.4% of the dose.The metabolites of FY-10 in bile after oral administered at dose of 12μg?kg-1 to rats were detected using an LC/MS/MS and ion trap methods under positive and negative ionization modes with multiple scan modes, such as full scan, product ion scan, precursor ion scan, neutral loss scan, SIM and SRM. None metabolite besides FY-10 was found. However, when we increase the dose to 40μg?kg-1, glucuranited metabolite was found in rat bile.4. Pharmacokinetic study on levodropropizine in healthy volunteers. The plasma harvested from healthy volunteers after an oral administration with levodropropizine (60 mg) was analyzed by a validated LC/MS/MS method. The pharmacokinetics parameters were calculated according to the concentration time curve. The results obtained were found to be similar with those reported.Conclusions:A fully validated LC/MS/MS method for the determination of FY-10 was developed and applied to the preclinical study in animals including dogs, mice and rats. With the aid of the method, a further investigation including absorption, distribution, metabolism and excretion on FY-10 was fulfilled and the results obtained will be valuable for its use in the clinic.A fully validated LC/MS/MS method for the determination of levodropropizine was developed and applied to the pharmacokinetic study in 20 healthy volunteers. The two methods exhibit a good linear and accurate, rapid and sensitive. They can meet the need for the pharmacokinetic study.
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