ABSTRACT
Objective To develop and validate a LC-MS/MS method for determination of rhoifolin in rat plasma and investi?gate its pharmacokinetic properties after intravenous administration to rats. Methods The analyte was isolated from rat plasma by liq?uid-liquid extraction with ethyl acetate. Separation was performed on a Phenomenex C8 column(30 mm×2.00 mm,3μm)with gradient elution using water-methanol as mobile phase. Electrospray ionization(ESI)was adopted in the negative ion mode for multiple reaction monitoring(MRM). The mass transitions were m/z 577.6→269.1 for rhoifolin,and m/z 271.0→151.0 for naringenin(internal stan?dard),respectively. Results The method showed good linearity over the range of 1-2000μg/L. Intra and inter-day precisions were both less than 10%,the relative error was within ± 7%. The extraction recoveries of three concentrations (low,middle and high) ranged from 86.8%to 91.0%. Main pharmacokinetic parameters were calculated by DAS 2.0. AUC0-t was(72627.8± 18067.9)μg·min/L, t1/2 was(52.1±14.3)min and CLz was(0.07±0.02)L/(min·kg). Conclusion The established LC-MS/MS method is specific and sensi?tive,and can be applied to pharmacokinetic study of rhoifolin. The pharmacokinetic parameters show that rhoifolin is eliminated rapid?ly in rats.
ABSTRACT
Assessment of QTc prolongation is a critical step for small molecule drug development.ICH S7B continues to be the main frame to guide the assessment for this potential cardiovascular risk.The ICH guideline outlines a 3-step approach to QTc prolongation,including in vitro bERG inhibition,ex vivo action potential duration (APD),and in vivo animal telemetry approch.Dog,monkey,swine,rabbit,ferret,and guinea pig are the common laboratory animals used for in vivo electrophysiology studies,especially using conscious Beagle Dog. In addition to all these guideline standard studies,many newly developed approaches,such as receptor binding for hERG inhibition,ex vivo methods such as perfused rabbit heart or guinea pig heartare are useful models for this purpose.All these methods display good correlation to clinic outcomes,and are low cost and have rapid turn-around time in nature; so that,they can help rapidly and predict this potential cardiac liability,resulting into accelerating process for small molecule drug candidate development.
ABSTRACT
Nonclinical safety evaluation plays a critical role in the process of new drug development.International Conference on Harmonization (ICH) guideline M3 (R2) provides a key direction for the nonclinical safety evaluation process.Proper strategies and toxicological studies should be considered together to move the drug candidates forward efficiently and quickly to support clinical plans and market registration.Updates on ICH guidelines,such as ICH S6 and ICH S9,have great impact on the direction of development.With the increasing cost of development and competition in the industry,elements like predictivity,animal models,and regulatory compliance are also very important in the process.Therefore,an insight into all these factors is essential to toxicologists in the safety evaluation process.The ability to use the overall knowledge will result in a quicker and better new drug development program.