Human protein tyrosine kinases play an essential role in carcinogenesis and have been recognized as promising drug targets. By the end of 2012, eight small molecule tyrosine kinase inhibitors (TKIs) have been approved by State Food and Drug Administration of China for cancer treatment. In this paper, the pharmacokinetic characteristics (absorption, distribution, metabolism and excretion) and drug-drug interactions of the approved TKIs are reviewed. Overall, these TKIs reach their peak plasma concentrations relatively fast; are extensively distributed and highly protein bound (> 90%); are primarily metabolized by CYP3A4; most are heavily influenced by CYP3A4 inhibitors or inducers except for sorafenib; are mainly excreted with feces and only a minor fraction is eliminated with the urine; and are substrate of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Additionally, many of the TKIs can inhibit some CYP450 enzymes, UGT enzymes, and transporters. Gefitinib, erlotinib, dasatinib, and sunitinib are metabolized to form reactive metabolites capable of covalently binding to biomolecules.

Chlorogenic acid (5-CQA) is one of the major components in some Chinese herbal injections. However, the metabolism of 5-CQA in rats after intravenous injection has not been determined. An ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) method was applied to identify the metabolites in bile, urine, feces and plasma after a single intravenous administration of 10 mg x kg(-1) 5-CQA to rats. Using MSE and mass defect filter techniques, a total of 35 metabolites were detected in bile, urine, feces and plasma. The predominant metabolites in bile were glutathione conjugates of O-methyl-5-CQA, accounting for approximately 80% of the metabolites excreted in bile. The major components in urine were parent drug, O-methyl-5-CQA, hydrolyzed metabolites and glucuronide conjugates. The major components in feces were O-methyl-5-CQA and its cysteine conjugates. The major component in plasma was the parent drug. The urinary and fecal excretion pathways were equally important to 5-CQA in rats. These results demonstrate that 5-CQA undergoes extensively metabolism in rats and are highly reactive to nucleophiles such as GSH. This finding indicates that attention should be paid on the injections containing 5-CQA, which may covalently bind to proteins, leading to allergenic drug reactions.

Aim To establish the pharmacokinetic principles of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral route based on the release kinetics of the dosage forms and the intrinsic pharmacokinetic parameters of the active drug, such as the rate constants of the absorption and elimination, and the distribution volume of the drug. Methods By the Laplace transform and the compartmental analysis method, the pharmacokinetic behaviors of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral routes were deduced with divisions of the dose being absorbed during the release phase and after the release has terminated. Results The pharmacokinetics of the non-parenteral administration of the zero-order release and the first-order release of mono-compartment drugs were established. Conclusion The pharmacokinetic theories of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral route have been established. Since the zero-order release and the first-order release are the primary release patterns, the theory should be a key to explore the pharmacokinetics of the controlled/sustained release dosage forms.

A chiral LC-MS/MS method for the simultaneous analysis of desvenlafaxine (DVS) enantiomers in human plasma was developed and applied to a pharmacokinetic study on 12 Chinese healthy volunteers. d6-Desvenlafaxine was used as internal standard (IS). Chromatographic separation was performed on the Astec Chirobiotic V chiral column (150 mm x 4.6 mm, 5 μm). The assay was linear over the concentration range of 0.500-150 ng x mL(-1) for both enantiomers (r2 > 0.99). The method was successfully applied to a stereoselective pharmacokinetic study of 100 mg desvenlafaxine sustained release tablets on 12 Chinese healthy volunteers under fasting conditions. The results showed that the pharmacokinetic parameters were similar to both enantiomers in Chinese healthy volunteers. The AUC(0-t), and C(max) of the two enantiomers were about 1.5 times higher than those of blacks and whites reported in the literature.

This study is to establish physiologically based pharmacokinetic (PBPK) models of famitinib in rat and monkey, and then to predict the pharmacokinetics and tissue distribution of famitinib in human based on the PBPK models. According to published paper, previous studies and the chemical properties of famitinib predicted by ACD/ADME suite and SimCYP, the PBPK models of rat and monkey were established and optimized using GastroPlus. And then, the PBPK models were applied to predict the pharmacokinetic and tissue distribution of famitinib in human. The results showed that the PBPK models of rat and monkey can fit the observed data well, and the AUC0-∞, ratios of observed and calculated data in rat and monkey were 1.00 and 0.97, respectively. The AUC0-∞, ratios of observed and predicted data in human were 1.63 (rat to human) and 1.57 (monkey to human), respectively. The rat and monkey PBPK models of famitinib were well established, and the PBPK models were applied in predicting pharmacokinetic of famitinib in human successfully. Hence, the PBPK model of famitinib in human could be applied in future drug-drug interaction study.

The study aims to evaluate the bioequivalence of valsartan hydrochlorothiazide tablets, and to investigate the potential cause of bioinequivalence. This was a single-center study with an open, randomized double-way crossover design. Test and reference preparations containing 160 mg of valsartan and 25 mg of hydrochlorothiazide were given to 36 healthy male volunteers. Plasma concentrations of valsartan and hydrochlorothiazide were determined simultaneously by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated, while the bioequivalence between test and reference preparations were evaluated. The dissolution profiles of test and reference preparations in four different mediums were determined via dissolution test and HPLC. The similarity was investigated according to the similarity factors (f2). The F(o-t) and F(0-infinity) were (139.4 +/- 65.2)% and (137.5 +/- 61.2)% for valsartan of test preparations. It led to get the conclusion that test and reference preparations were not bioequivalent for valsartan. A significant difference was observed between test and reference tablets in the valsartan dissolution test of pH 1.2 hydrochloric acid solution. The key factor of the bioinequivalence might be that dissolution of valsartan in acid medium has marked difference between two preparations.

To study the metabolite excretion of theophylline, a rapid and specific method by liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) method for simultaneous determination of theophylline, 1, 3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX) and 1-methyluric acid (1-MU) in human urine was developed using theophylline-d6 and 5-fluorouracil as internal standards. Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the negative mode for mass spectrometric detection. After diluted with methanol and centrifuged, the analytes and ISs were separated on a XDB-Phenyl (150 mm x 4.6 mm, 5 microm) column with a mixture of water-methanol-formic acid (30 : 70 : 0.15) as mobile phase at a flow rate of 0.6 mL x min(-1). The linear calibration curves for theophylline, 1, 3-DMU, 3-MX and 1-MU were obtained in the concentration range of 1.0-250 microg x mL(-1), separately. The method herein described is effective and convenient, and can be used for determination of theophylline and its three metabolites. The results showed that urinary excretion ratio of theophylline, 1,3-DMU, 3-MX and 1-MU is approximately 1 : 3 : 1 : 2 in Chinese subjects, which is similar to the reported excretion pattern in Caucasian.

The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.

A sensitive, rapid and accurate liquid chromatography-tandem mass spectrometric (LC-MS/MS) method with pre-column derivatization was developed for the simultaneous determination of erdosteine and its thiol-containing active metabolite in human plasma. Paracetamol and captopril were chosen as the internal standard of erdosteine and its active metabolite, respectively. Aliquots of 100 microL plasma sample were derivatized by 2-bromine-3'-methoxy acetophenone, then separated on an Agilent XDB-C18 (50 mm x 4.6 mm ID, 1.8 microm) column using 0.1% formic acid methanol--0.1% formic acid 5 mmol x L(-1) ammonium acetate as mobile phase, in a gradient mode. Detection of erdosteine and its active metabolite were achieved by ESI MS/MS in the positive ion mode. The linear calibration curves for erdosteine and its active metabolite were obtained in the concentration ranges of 5-3 000 ng x mL(-1) and 5-10 000 ng x mL(-1), respectively. The lower limit of quantification of erdosteine and its active metabolite were both 5.00 ng x mL(-1). The pharmacokinetic results of erdosteine and its thiol-containing active metabolite showed that the area under curve (AUC) of the thiol-containing active metabolite was 6.2 times of that of erdosteine after a single oral dose of 600 mg erdosteine tables in 32 healthy volunteers, The mean residence time (MRT) of the thiol-containing active metabolite was (7.51 +/- 0.788) h, which provided a pharmacokinetic basis for the rational dosage regimen.

AIM　To assess the pharmacokinetic profile of single doses of meloxicam in healthy Chinese volunteers. METHODS　The plasma concentrations of meloxicam after an oral dose of 15 mg to twenty healthy male volunteers were analized by means of a validated HPLC method. The pharmacokinetic parameters were subjected to Shapiro-Wilk test to determine whether these data were fitted to a normal distribution. RESULTS The twenty volunteers can be classified into extensive metabolizers and poor metabolizers according to pharmacokinetic parameters. The main parameters in the two groups obtained were as follows: T1/2 were 21±4 and 38±9 h, AUC0-∞ were 49±10 and 110±8 μg*h*mL-1, respectively. Even the AUC data in extensive metabolizers were 1.7 times as that reported in White volunteers following the same doses of meloxicam. CONCLUSION　There were significant individual differences in the pharmacokinetics of meloxicam in Chinese volunteers, which may be due to the genetic polymorphism of CYP2C9.