ABSTRACT
@#The metabolic stability test of drugs is a key step in drug discovery and achieving low clearance is frequently the goal in the design of drug. Increased drug metabolism stability can reduce drug dosage, enhance drug exposure and prolong drug half-life. Accurately assessing the metabolic stability parameters of low clearance drugs and predicting human pharmacokinetics has become a challenge. Traditional tools in vitro including microsomes and suspended primary hepatocytes are limited by incubation time, which is not long enough to make sufficient metabolic conversion. Determination of intrinsic clearance or metabolic pathways and mechanisms of drug are implicated. Novel models tend to further mimic the in vivo environment in order to prolong lifetime of hepatocytes and achieve sufficient metabolic turnover of drugs for monitoring. In vitro-in vivo correlation of intrinsic clearance of methodologies has evaluated to support the reliability in predicting human pharmacokinetics. Application of these methodologies greatly decreases the forthputting of experimental animals and the release of expensive clinical trials during the acquisition of pharmacokinetic parameters. In this review, we summarized the principles, advantages and disadvantages of the novel in vitro methodologies for metabolic stability dealing with low-turnover drugs, including hepatocyte relay method, plated human hepatocytes, coculture system and microfluidic devices. Future prospect is proposed for in vitro metabolic models and it provides reference and optimization in metabolic stability for early lead compounds.
ABSTRACT
Objective To research the influences of gambogic acid on rats'cytochrome P450 isoforms by using the Cocktail probe drugs. Methods Rats were randomly divided into several groups. One group of rats received gambogic acid solution containing 0.5 %CMC-Na (2 mg?mL-1,once per day) orally for six days. At the same time,the rats in the other group received 0.5 %CMC-Na solution serving as blank control group. Blood samples were collect at different time point,and the plasma concentration of cocktail probe drugs was determined by HPLC. Results There was insignificant difference of caffeine and dapsone metabolism between the gambogic acid group and the blank group,but the chlorzoxazone was eliminated faster in the gambogic acid group,and the half life of chlozoxazone was shorter. Conclusion Gambogic acid has no significant influence on the cytochrome P450 isoforms of CYP1A2 and CYP3A4,but has an induction on the CYP2E1.