A sensitive LC-MS/MS method for simultaneous determination of cabozantinib and its metabolite cabozantinib N-oxide in rat plasma and its application in a pharmacokinetic study.

Cabozantinib (CBZ) is used for the treatment of progressive, metastatic medullary thyroid cancer. Its major oxidative metabolite is cabozantinib N-oxide (CBN), which contains a structural alert associated with mutagenicity, yet the pharmacokinetics studies lack the simultaneous investigation of CBN and dose proportionality. In the current study a simple LC-MS/MS method was developed and validated for the simultaneous estimation and pharmacokinetic investigation of CBZ and CBN in rat plasma. The analytes were separated on a Waters Atlantics C18 column (2.1 × 150 mm, 3 µm). The mass spectrometry analysis was conducted in positive ionization mode with multiple reaction monitoring. Good linearity was observed over the concentration ranges of 0.500-5000 ng/mL for CBZ and 0.525-2100 ng/mL for CBN. The extraction recoveries were constant and the intra- and inter-batch precision and accuracy were acceptable for the analysis of biological samples. The method was successfully applied for the simultaneous estimation of CBZ and CBN in a pharmacokinetic study in Sprague-Dawley rats. After oral administration of CBZ (1, 5 and 12.6 mg/kg), although CBZ showed dose proportionality, the metabolite CBN showed obvious nonlinear elimination pharmacokinetics with greater than dose-proportional increases in exposure.

Pharmacokinetic and bioequivalence comparison of a single 100-mg dose of cefteram pivoxil powder suspension and tablet formulations: a randomized-sequence, open-label, two-period crossover study in healthy Chinese adult male volunteers.

BACKGROUND: Cefteram pivoxil (CFTM-PI) is an oral antibiotic available in powder suspension and tablet formulations indicated in China for the treatment of bacterial infections. Although these 2 formulations are marketed in China, published information regarding their pharmacokinetics and bioequivalence in the Chinese population is not available. OBJECTIVE: The aim of this study was to compare the pharmacokinetics and bioequivalence of the powder suspension (test) and tablet (reference) formulations of CFTM-PI 100 mg available in China. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 100-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Plasma was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including C(max), AUC from time 0 (baseline) to 6 hours (AUC(0-6)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were obtained at intervals over the 6-hour period after study drug administration. The formulations were considered bioequivalent if the log-transformed ratios of C(max) and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events (AEs). RESULTS: Twenty-four Chinese male subjects (mean [range] age,24.2 [23-32] years;weight,64.3 [58-67] kg; height, 172 [167-185] cm) enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of C(max), AUC(0-6;), and AUC(0-infinity) were 96.5 to 120.1, 95.7 to 110.2, and 96.2 to 110.4, respectively (all, P>0.05). Similar results were found for the data without log-transformation. No AEs occurred or were reported during the study. CONCLUSIONS: In this small study in healthy Chinese adult male volunteers, a single 100-mg dose of the powder-suspension formulation was bioequivalent to a single 100-mg dose of the tablet formulation based on the US FDA's regulatory definition (rate and extent of absorption). Both formulations were well tolerated.

Determination and stress studies on YK-1101, a potential histone deacetylase, by HPLC-UV and HPLC-TOF/MS methods.

YK-1101, with its structure as S-((E)-4-((7S,10S,Z)-4-ethylidene-7-isopropyl-2,5,8,12-tetraoxo -9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-dien-10-yl)but-3-en-1-yl) ethanethioate, is synthesized as a potential histone deacetylase inhibitor. Its quality and stability under various stress conditions are not fully understood. In this study, a high performance liquid chromatographic (HPLC) method was established and validated for the analysis of YK-1101 bulk drug samples. The chromatographic separation was performed on a C18 column with acetonitrile and water as mobile phase in a gradient elution. Based on the established method, the stability studies of YK-1101 under various stress conditions were carried out. YK-1101 was shown to undergo degradation under basic and acidic stress conditions, while it was stable under oxidative, photolytic and thermal conditions. In addition, a time of flight mass spectrometer (TOF/MS) was coupled to HPLC for the characterization of major degradation products produced under basic and acidic stress conditions. Their degradation pathways were also discussed.

Synthesis and in vitro cytotoxicity evaluation of baicalein amino acid derivatives.

AIM: To synthesize the baicalein amino acid derivatives and evaluate their cytotoxicity activities in vitro. METHODS: Amino acids were subjected to methylation and aminoacylation reaction, then reacted with formaldehyde and baicalein to synthesize baicalein-8 benzyl amino acid derivatives. Through carboxyl group protection and aminoacylation of amino acid and benzyl protection of baicalein, derivatives of baicalein-6-O-amino acid esters were obtained. All of the target compounds were identified by IR, MS and (1)H NMR. RESULTS: Thirteen novel derivatives were synthesized and characterized. Their cytotoxic activities were assessed by the MTT method on the inhibition of HepG2 cells in vitro. CONCLUSION: Compounds 4c, 4d, 7a and 7b showed a significant increase in cytotoxicity compared with baicalein.

Characterization of (68)Zn uptake, translocation, and accumulation into developing grains and young leaves of high Zn-density rice genotype.

Zinc (Zn) is an essential micronutrient for humans, but Zn deficiency has become serious as equally as iron (Fe) and vitamin A deficiencies nowadays. Selection and breeding of high Zn-density crops is a suitable, cost-effective, and sustainable way to improve human health. However, the mechanism of high Zn density in rice grain is not fully understood, especially how Zn transports from soil to grains. Hydroponics experiments were carried out to compare Zn uptake and distribution in two different Zn-density rice genotypes using stable isotope technique. At seedling stage, IR68144 showed higher (68)Zn uptake and transport rate to the shoot for the short-term, but no significant difference was observed in both genotypes for the long-term. Zn in xylem sap of IR68144 was consistently higher, and IR68144 exhibited higher Zn absorption ratio than IR64 at sufficient (2.0 µmol/L) or surplus (8.0 µmol/L) Zn supply level. IR64 and IR68144 showed similar patterns of (68)Zn accumulation in new leaves at seedling stage and in developing grains at ripening stage, whereas (68)Zn in new leaves and grains of IR68144 was consistently higher. These results suggested that a rapid root-to-shoot translocation and enhanced xylem loading capacity may be the crucial processes for high Zn density in rice grains.

Uptake, translocation, and remobilization of zinc absorbed at different growth stages by rice genotypes of different Zn densities.

Zinc (Zn) is an essential micronutrient for humans, and increasing Zn density in rice ( Oryza sativa L.) grains is important for improving human nutrition. The characteristics of Zn translocation and remobilization were investigated in high Zn density genotype IR68144, in comparison with the low Zn density genotype IR64. Stable isotope tracer (68)Zn was supplied at various growth stages, either to the roots in nutrient solution or to the flag leaves to investigate the contribution of (68)Zn absorbed at different growth stages to grain accumulation and the remobilization ability of (68)Zn within plants. Significant differences in (68)Zn allocation were observed between the two rice genotypes. Much higher (68)Zn concentrations were found in grains, stems, and leaves of IR68144 than in IR64, but higher (68)Zn was found in roots of IR64. More than half of the Zn accumulated in the grains was remobilized before anthesis, accounting for 63 and 52% of the total Zn uptake for IR68144 and IR64, respectively. Without supply of external Zn, at vegetative or reproductive stages, more (68)Zn was retranslocated from "old tissues" to "new tissues" in IR68144 than in IR64. Retranslocation of (68)Zn from flag leaves to grains was twice as high in the former when (68)Zn was applied to the flag leaves during booting or anthesis. These results indicate that Zn density in rice grains is closely associated with the ability to translocate Zn from old tissues to new tissues at both early and late growth stages and with phloem remobilization of Zn from leaves and stems to grains.