The chromatographic capacity factors (k IAM ) of 23 structurally diverse drugs were measured by the immobilized artificial membrane (IAM) phosphatidylcholine chromatography for the prediction of blood-brain barrier (BBB) penetration. The k IAM was determined using the mobile phase consisting of acetonitrile:DPBS (20:80 v/v) and corrected for the molar volume of the solutes (k IAM /MW n ). The correlation between k IAM /MW n and CNS penetration was highest when measured at pH 5.5 with the power function of n = 4. This in vitro prediction method was validated with 7 newly synthesized PDE-4 inhibitors. The relationship between in vivo plasma-to-brain concentration ratios and in vitro CNS penetration was excellent (r = 0.959). The developed in vitro prediction method may be used as a rapid screening tool for BBB penetration of drugs with passive transport mechanism, with high success, low cost, and reproducibility. (Journal of Biomolecular

A physiologically based pharmacokinetic (PBPK) model consisting of vein, artery, lung, liver, spleen, kidneys, heart, testes, muscle, brain, adipose tissue, stomach, and small intestine was developed to predict the tissue distribution and blood pharmacokinetics of bisphenol A in rats and humans. To demonstrate the validity of the developed PBPK model, bisphenol A was administered to rats by multiple iv injections to steady state. The PBPK model predicted the steady-state levels of bisphenol A in blood and various tissues observed in rats after multiple iv injections. The PBPK model was further applied to predict blood and various tissue levels of bisphenol A in a 70 kg-human after single iv injection (5-mg dose) and multiple oral administrations to steady state (100-mg doses every 24 h). The simulated steady-state human blood levels (0.9-1.6 ng/ml) were comparable to basal blood levels of bisphenol A reported in literature (1.49 ng/ml). Furthermore, pharmacokinectic parameters of CL (116.6 L/h), Vss (141.8 L), and t1/2 (76.8 min) predicted for humans were comparable to those previously predicted by simple allometric scaling. This PBPK model may provide insights into the tissue distribution characteristics as a result of human exposure to bisphenol A.

This study is the first report of the pharmacokinetics of a novel histone deacetylase inhibitor, apicidin, in rats after i.v. and oral administration. Apicidin was injected intravenously at doses of 0.5, 1.0, 2.0 and 4.0 mg/kg. The terminal elimination half-life (t1/2), systemic clearance (Cl) and steady-state volume of distribution (Vss) remained unaltered as a function of dose, with values in the range 0.8-1.1 h, 59.6-68.0 ml/min/kg and 2.4-2.7 l/kg, respectively. Whereas, the initial serum concentration (C0) and AUC increased linearly as the dose was increased. Taken together, the pharmacokinetics of apicidin were linear over the i.v. dose range studied. The extent of urinary and biliary excretion of apicidin was minimal (0.017%-0.020% and 0.049% +/- 0.016%, respectively). Oral pharmacokinetic studies were conducted in fasting and non-fasting groups of rats at a dose of 10 mg/kg. The Tmax, Cl/F and Vz/F were in the range 0.9-1.1 h, 520.3-621.2 ml/min/kg and 67.6-84.4 l/kg, respectively. No significant difference was observed in the oral absorption profiles between the two groups of rats. Apicidin was poorly absorbed, with the absolute oral bioavailability of 19.3% and 14.2% in fasting and non-fasting rats.

No abstract

Apicidin, a fungal metabolite isolated from Fusarium pallidoroseum, is a cyclic tetrapeptide that exhibits potent anti-protozoal and anti-angiogenic activities. Although extensive studies have been recently conducted to examine the biological and pharmacological action, no information is available on the quantitative analysis of apicidin. To our knowledge, this study is the first to describe a rapid and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay method for the quantification of apicidin in rat serum. The method was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification (LLOQ), accuracy, and precision. The multiple reaction monitoring was based on the transitions m/z 624.7 --> 84.3 and 372.1 --> 176.1 for apicidin and trazodone, respectively. The assay utilized a single liquid-liquid extraction and isocratic elution, and the LLOQ was 0.5 ng/mL using 0.1 mL of rat serum. The assay was linear over a range from 0.5-1000 ng/mL, with correlation coefficients >0.9994. The mean intra- and inter-day assay accuracy ranged from 99.9-101.5% and 94.8-102.1%, respectively, and the mean intra- and inter-day precision was between 2.7-5.9% and 1.6-11.5%, respectively. The developed assay method was applied to a pharmacokinetic study after intravenous injection of apicidin in rats at a dose of 1 mg/kg.