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Preclinical Pharmacokinetics Dynamics Of The Hydrochloric Phencynonate Levo Series Of Chiral Compounds Pharmacokinetic Characteristics Of Rapid Prediction

Posted on:2008-11-15Degree:MasterType:Thesis
Country:ChinaCandidate:J L LiFull Text:PDF
GTID:2204360215960632Subject:Pharmacology
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L—8021 (L—Phencynonate Hydrochloride) was a novel anti-cholinergic drug developed by our Institute of Pharmacology and Toxicology, which is more active than the racemic in their pharmacological potencies as anticholinergic agents for anti-areolae in inhibiting oxotremorine-induced salivation and inhibiting the contractile response to carbachol.The liquid chromatographic - tandem mass spectrometric (LC -MS/MS) method using methanol to precipitate protein was developed for the determination of phencynonate in biological specimen and fully validated for the selectivity, accuracy, precision and stability etc.In the present study, experiments have been done to investigate the pharmacokinetics of L-8021 which has been given three different dosages in rats and Beagles; to investigate the distribution of L-8021 in the models of mice; to preliminarily explore the excretion and biotransformation of L-8021 in rats; to study the plasma protein binding of L-8021 in vitro; Valuable parameters obtained from the experiments have successfully explained the dynamic process of L-8021 in the animal's body, which provided the reference for further study.The research results reported as follows:1. L—8021 was dose-dependent within the range of 0. 5~8mg/kg in rats and the blood drug concentration-time curves were all best fitted to first order absorption two-compartment open model after via po administration of three different dosages.2. L—8021 was dose-dependent within the range of 0. 5~8mg/kg in Beagles and the blood drug concentration-time curves in Beagles were all best fitted to first order absorption two-compartment open model after via po administration of three different dosages.3. Following oral administration to Beagles, the absolute bioavailability of L-8021 was 17.82%, which was very low and resulted from poor absorption.4. Following oral administration to Beagles, L-8021 was fast in absorption, distribution and elimination. Drug concentration in Liver, spleen and lung reached the peak more quickly than in other tissues and decreased to very low level in 120 minute.5. The recovered L-8021 detected in the urine and in the faeces was very little and only 3. 44‰of the total appeared. L-8021 in vivo was mainly eliminated probably through biotransformation.6. L-8021 was highly binding with the plasma of human and Beagle and the mean binding rate was above 85%, which probably influences the drug concentration of the target tissues.7. Following oral administration to rats, m/z 372, 374, 360, 388, and 390 besides L-8021 detected in the urine were probable metabolites of L-8021, which was to be further confirmed.8. The two optical isomers of An11 as well as Ethl6 were found to be different in metabolism stability and the S-type-compound was more stable than the R-type-compound.9. The substituting group in the benzene ring of the compounds may influence absorption of the compounds; the localization of the substituting group in the benzene ring of the compounds may influence absorption of the enantiomers; the polarity of the substituting group in the benzene ring of the compounds may influence elimination of the enantiomers.
Keywords/Search Tags:L-8021, LC/MS/MS, enantiomer, pharmacokinetics, absorption, distribution, biotransformation
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