Xiao Wei Teng

Pharmacokinetics of selected stilbenes: rhapontigenin, piceatannol and pinosylvin in rats.

The pharmacokinetics of piceatannol, pinosylvin and rhapontigenin were characterized in male Sprague‐Dawley rats after single intravenous doses of 10 mg kg−1 of each stilbene. Serial blood samples were collected via a catheter inserted into the right jugular vein and plasma samples were analysed for the selected stilbenes concentrations using reverse phase HPLC methods. After an acute intravenous dose of piceatannol, plasma AUC, urine t½, CL and Vd were 8.48 ± 2.48 μgh mL−1, 19.88 ± 5.66 h, 2.13 ± 0.92 Lh−1 kg−1 and 10.76 ± 2.88 Lkg−1 (mean ± s.e.m.), respectively. The acute intravenous dose of pinosylvin yielded the plasma AUC, urine t ½, CL and Vd values of 5.23 ± 1.20 μgh mL−1, 13.13 ± 2.05 h, 1.84 ± 0.44 Lh−1 kg−1 and 2.29 ± 0.56 Lkg−1 (mean ± s.e.m.), respectively. Rhapontigenin intravenous dosing yielded the plasma AUC, urine t½, CL and Vd values of 8.39 ±0.10 μgh mL−1, 25.31 ± 1.46 h, 1.18 ± 0.035 Lh−1 kg−1 and 11.05 ± 0.17 Lkg−1 (mean ± s.e.m.), respectively. Each stilbene was extensively glucuronidated. These stilbenes were predominantly eliminated via non‐urinary routes. All three stilbenes were highly distributed into tissues and were highly extracted by the liver. The detectable plasma half‐lives of these xenobiotics appear to be relatively short. However, utilizing urinary concentration‐time data, much longer elimination half‐lives were evident. The estimates of oral bioavailability characterize these stilbenes as poorly bioavailable compounds.

Degradation kinetics of mometasone furoate in aqueous systems

Mometasone furoate (MF) is a synthetic glucocorticoid. There is little information available on the stability of MF and no degradation products have been unequivocally identified. Thus, the primary objective of this study was to characterize the degradation of MF, qualitatively and quantitatively. Stability of MF decreased with increasing pH (>4) and decreasing ionic strength in aqueous media. The chemical stability of MF in aqueous systems was significantly dependent on pH. MF appeared to be stable at pH < 4 but degraded to four products at higher pH. The degradation of MF in aqueous solutions follows pseudo-first-order kinetics and involved a series of parallel and consecutive reactions. The turnover of MF and its products appears to be catalyzed by the hydroxide ion. The pH dependence of these reactions should be considered, when formulating or extemporaneously compounding MF formulations. An optimal pH of stability was below pH 4. The changes in pH, however, do not appear to be the only factor of importance, since an increase in ionic strength and buffer concentration displayed a stabilizing effect on this glucocorticoid in the buffers tested. Trace metal ions are unlikely to be involved in degradation of MF in aqueous solution.

Stereospecific high-performance liquid chromatographic analysis of flurbiprofen: application to pharmacokinetic studies.

A method of analysis of flurbiprofen (+/- 2-(2-fluoro-4-biphenyl)-propionic acid) in biological fluids is necessary to study the kinetics of in vitro and in vivo metabolism and tissue distribution. A simple high-performance liquid chromatographic method was developed for simultaneous determination of flurbiprofen enantiomers in rat serum. Serum (0.1 ml) was extracted with 2,2,4-trimethylpentane-isopropanol (95:5, v/v) after addition of the internal standard (IS), S-naproxen and acidification with H(2)SO(4). Separation was achieved on a Chiralpak AD-RH column with UV detection at 247 nm. The calibration curve was linear ranging from 0.05 to 50 microg/ml for each enantiomer. The mean extraction efficiency was >95%. Precision of the assay was <11% (CV), and was within 12.6% at the limit of quantitation (LOQ) (0.05 microg/ml). Bias of the assay was lower than 13.1%, and was within 12.8% at the LOQ. The assay was applied successfully to the in vivo kinetic study of flurbiprofen in rats.

Kinetics of metabolism and degradation of mometasone furoate in rat biological fluids and tissues

Mometasone furoate (MF) is a potent glucocorticoid developed for the treatment of glucocorticoid‐responsive inflammatory disorders. The in‐vitro and ex‐vivo kinetics of the degradation and metabolism of MF were studied in selected biological fluids of rat and subcellular fractions of different rat tissues. In‐vitro, MF was found to degrade slowly into four products in serum and urine, and metabolized rapidly and extensively in rat liver, minimally in extrahepatic tissues, including intestine, stomach, lung and kidney. Further investigation found that the microsomal fraction was the major intracellular site of MF 6β‐hydroxylation in rat liver. Using chemical inhibitors, CYP3A was found to be the major enzyme involved in the in‐vitro MF 6β‐hydroxylation in rat liver microsomes. Enzyme kinetic studies in rat liver microsomes showed that the overall metabolic process of MF followed biphasic Michaelis‐Menten kinetics, while 6β‐hydroxylation obeyed monophasic Michaelis‐Menten kinetics. The kinetic parameters derived from the kinetic models along with the enzyme inhibition studies suggest that MF is mainly metabolized via 6β‐hydroxylation mediated by CYP3A primarily, and also biotransformed via other pathway(s) catalysed by other enzymes in rat liver in‐vitro.