Studies On The Pharmacokinetics Of CYC-116

CYC-116 is a new chemical with anticancer activity. In this paper, methods for concentration assay of this drug in biological matrix were developed, and the pharmacokinetic processes of CYC-116 in vivo were systematically studied.1. For further evaluation of effect of the temperature on the degradation of CYC-116, the concept of chemical kinetics and Arrhenius equations was introduced to investigate the degradation kinetics of CYC-116 in aqueous solutions at 37, 60, 80, 100? with pH 1.5-12.5, combining to the effect of pH value. A RP-HPLC method was developed for determining CYC-116. The concentrations of the remaining CYC-116 determined at the different time intervals were used in the plots. The plots were: (a)values of concentration against time (zero-order kinetics), (b) In of concentration versus time (first-order kinetics) and (c) reciprocal of concentration versus time (second-order kinetics). The regression coefficients (r) obtained indicated a first-order reaction rate law under all conditions. The isothermal prediction method was used to calculate Arrhenius equations under different pH conditions. The Ea were: 82.1, 37.78, 38.27,38.77, 45.85 kJ·mol-1 .This study reveals that the degradation of CYC-116 is a temperature-dependent and pH-dependent reaction.2. An HPLC-UV method and an HPLC-MS method, which were rapid, accurate and sensitive enough with the LLOQ of 50 ng·mL-1 and 5 ng·mL-1, respectively, were developed and fully validated for the pharmacokinetic study of CYC-116 in rats.3. The pharmacokinetic processes of CYC-116 in rats after an intravenous injection(5 mg·kg-1) and an oral administration with different doses (5, 10, 20 mg·kg-1) With the oral doses of 5, 10, 20 mg·kg-1, pharmacokinetic parameters obtained in male rats were as follows: Cmax were 313.6 ± 186.2,700.1 ± 131.9 and 1403 ± 288; Tmax were 1.42 ±0.90, 1.29± 0.33 and 1.96 ± 1.05; AUC(0-t) were 739.7 ± 559.4, 1879.0 ±658 and 4287± 1166; t1/2 were 2.06 ± 1.61,1.21 ± 0.53 and 1.45 ± 0.81,respectively. The parameters obtained were then compared and analyzed. Dose-dependent linear relationships of AUC0-t and Cmax for CYC-116 was found in the range of 5 to 20 mg-kg-1 after oral administration to rats.After intravenous injection and oral administration of 5 mg·kg-1, the drug reached its maximum concentration of Cmax were 689.1 ± 459.4 ?g·L-1 and 6724 ± 1241 ?g·L-1;AUC(0-t) were 2.907 ± 1.475×103 ?g·h·L-1 and 17.00 ± 6.45×103 ?g·h·L-1; ti/2 were 2.53 ±1.27 h and 2.72 ± 1.77 h,respectively. Poor absolute bioavailability may due to oral absorption and hepatic first pass effect.4 The tissue distribution of CYC-116 in rats after an oral administration of 10 mg·kg-1 was investigated. 45 min after drug administration, CYC-116 was broadly distributed in all the tissues examined. The times of peak drug concentration of most tissues were located at 2.5 h after dosing. After 6 h, the tissue concentration of CYC-116 decreased. The highest value presented in intestine and stomach at 45min after dosing might due to the way of drug administration. Tissue-specific distributions were observed, the liver, lung, fat, kidney, and pancreas manifested as the dominant organs with high tissue concentrations which might be responsible for large volume of blood flow. Except the small intestine and stomach, the amount of CYC-116 is the largest in the liver. The presence of drug in the brain indicated that CYC-116 could penetrate the blood brain barrier.5. After an oral administration of 10 mg·kg-1 the cumulative amount for CYC-116 were 376.1 ± 138.?g for rats in feces after administration,which amounted 16.7% of the given dosage. We didn't find CYC-116 in the bile and urine. Link-rat model study showed that enteropatic recycling of CYC-116 not important in rats.6. Using tandem mass spectrometry method to analysis the entire scan of CYC-116 in methanol solution under different collision energy of ion fragmentation information, I summarizes the fragmentation regularity of CYC-116 under ESI source. The work provide reference to its implications for the structure of metabolites in the rats. The metabolism of CYC-116 in rats in vivo and liver microsomes incubation solution in vitro has been studied systematically. Seven I phase metabolites and three II phase have been detected. CYC-116 were metabolized primarily in the liver...