| Pharmacokinetic(Pharmacokineties,PK)is an important part of pharmacology,which studies the drug absorption,distribution,metabolism and excretion(ADME)in organism within a time process.The ideal drug candidates need not only strong pharmacological activities but also the effect of the appropriate action time and good bioavailability.In the process of the development of new drugs,the pharmacodynamics of candidate molecule is extremely important.Osteoporosis is a kind of systemic metabolic bone disorder,which is called a silent killer and is a major problem of aging society.Osteoporosis drugs available in current market are mainly divided into two categories:anti-resorptive and bone anabolic agents.Bisphosphonates is the main representative of anti-resorptive drugs in clinic.PTH 1-34 is the only clinically available bone anabolic drug for the treatment of osteoporosis,while,with dosing period limitation and side effects.Hence,development of anabolic agents for improving bone formation and bone repair has considerable social and economic impact.Oleanolic acid(OA)has extensive biological activity,our group have synthesized novel series of OA derivatives.Among the derivatives,a compound named K displayed a potent inhibitory effect on osteoporosis in vitro and in vivo.In this article,to understand the drugability of K,the pharmacokinetics and tissue distribution of K in rats are studied.1.Determination of K in rat plasma and pharmacokineties study of K in ratsTo establish a simple and sensitive method for quantification of K by LC-MS/MS and study the pharmacokineties of K in rats,K,and 8aIS as an internal standard(IS)in rat plasma samples were extracted by methanol and analyzed by LC-MS/MS after centrifugation.Methods:samples were analyzed with a gradient mobile phase system at a flow-rate of 0.5 mL/min on a Xbridge C18 column(2.1mm×50mm,2.5μm).Measurement of K was performed by positive ion electro spray ionization in multiple reaction monitoring mode,monitoring the transitions m/z 821.437→203.20 and m/z 582.271→409.300 for K and 8aIS,respectively.Results demonstrated that the linearity,sensitivity,specificity and so on met the requirements of biological samples analysis.Therefore,the developed method was applied to the current PK study.The rats were divided into groups and 6 rats per group.After oral administration of K(10mg/kg)to rats,the plasma drug concentration-curve analyzed by non-compartment model.The half-life was 2.415±0.391h.The Tmax was 3.2±0.837h.The AUC(0-t)was 180.33 ± 40.47μg/L*h.After intravenous administration of K(lmg/kg)to rats,the plasma drug concentration-curve analyzed by two-compartmental model.The distribution half-life time was 0.04 ± 0.008h,the elimination half-life time was 1.46±0.189h.The AUC(0-t)was 4306.61 ± 546.41μg/L*h.2.Tissue distribution study on KA method for the determination of K in rat tissues was developed using ultra-fast liquid chromatography-tandem mass spectrometry(UFLC-MS/MS).Eight tissues including heart,liver,spleen,kidney,stomach,jejunum,muscle and fat were measured at 3 different time points(1,3 and 10h).After administration of K,the jejunum and stomach had higher concentration than any other tissues.In most tissues,the concentration of K was the highest in each group at the time of 1h,while at 10h,K can be hardly found in the tissues.It shows that K can be rapidly spread and eliminated.The heart and spleen received more drug than other tissues,implied that K has a priority distribution in the organs of abundant blood flow.On the other hand,we found less K in liver that suggested a quick metabolism by liver.It is worth mentioning that the concentration in muscle was much more than those in others,which suggested there might be a certain interaction between muscle and bone. |
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