Dose- and time-dependent pharmacokinetics of apigenin trimethyl ether.

Apigenin trimethyl ether (5,7,4'-trimethoxyflavone, ATE), one of the key polymethoxyflavones present in black ginger (rhizome of Kaempferia parviflora) possesses various health-promoting activities. To optimize its medicinal application, the pharmacokinetics of ATE was assessed in Sprague-Dawley rats with emphases to identify the impacts from dose and repeated dosing on its major pharmacokinetic parameters. Plasma ATE levels were monitored by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Upon single intravenous administration (2 mg/kg), plasma levels of ATE declined through an apparent first-order process while dose-escalation to 4 and 8 mg/kg led to its non-linear disposition, which could be described by the Michaelis-Menten model. Similarly, dose-dependent oral pharmacokinetics was confirmed and when the dose was escalated from 5 to 15 and 45 mg/kg, much longer mean residence time (MRT0→last), higher dose-normalized maximal plasma concentration (Cmax/Dose) and exposure (AUC/Dose) were observed at 15 and/or 45 mg/kg. One-week daily oral administration of ATE at 15 mg/kg caused its accelerated elimination and the plasma exposure (AUC) after intravenous (2 mg/kg) and oral administration (15 mg/kg) dropped ~40 and 60%, respectively. As ATE displayed both dose- and time-dependent pharmacokinetics, caution is needed in the medicinal applications of ATE and/or black ginger.

Determination of Tangeretin in Rat Plasma: Assessment of Its Clearance and Absolute Oral Bioavailability.

Tangeretin (TAN) is a dietary polymethoxylated flavone that possesses a broad scope of pharmacological activities. A simple high-performance liquid chromatography (HPLC) method was developed and validated in this study to quantify TAN in plasma of Sprague-Dawley rats. The lower limit of quantification (LLOQ) was 15 ng/mL; the intra- and inter-day assay variations expressed in the form of relative standard deviation (RSD) were all less than 10%; and the assay accuracy was within 100 ± 15%. Subsequently, pharmacokinetic profiles of TAN were explored and established. Upon single intravenous administration (10 mg/kg), TAN had rapid clearance (Cl = 94.1 ± 20.2 mL/min/kg) and moderate terminal elimination half-life (t1/2 λz = 166 ± 42 min). When TAN was given as a suspension (50 mg/kg), poor but erratic absolute oral bioavailability (mean value < 3.05%) was observed; however, when TAN was given in a solution prepared with randomly methylated-ß-cyclodextrin (50 mg/kg), its plasma exposure was at least doubled (mean bioavailability: 6.02%). It was obvious that aqueous solubility hindered the oral absorption of TAN and acted as a barrier to its oral bioavailability. This study will facilitate further investigations on the medicinal potentials of TAN.

Quantification of apigenin trimethyl ether in rat plasma by liquid chromatography-tandem mass spectrometry: Application to a pre-clinical pharmacokinetic study.

Apigenin trimethyl ether (5,7,4'-trimethoxyflavone, ATE) is a naturally occurring polymethoxyflavone with a wide range of health-promoting activities. In this study, a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of ATE in rat plasma. Protein precipitation was applied as plasma clean-up procedure; the electrospray ionization was operated in its positive ion mode while ATE and formononetin (internal standard) were measured by multiple reactions monitoring (ATE: m/z 313.1→298.1; formononetin: 269.2→213.3). This LC-MS/MS method displayed good selectivity, sensitivity (lower limit of quantification=2.5ng/ml), accuracy (both intra- and inter-day analytical recovery within 100±10%) and precision (both intra- and inter-day RSD <10%). The matrix effect was found to be insignificant. The pharmacokinetic profiles of ATE were subsequently examined in Sprague-Dawley rats after single oral administration (10mg/kg). When given in an aqueous suspension, ATE was slowly absorbed with quite low plasma exposure (AUC). Fasting further attenuated its oral absorption and led to ∼70% drops in average maximal plasma concentration (Cmax) and AUC. When dosed in a solution formulated with 2-hydroxypropyl-ß-cyclodextrin, the oral absorption of ATE was substantially improved with ∼500% increases in average Cmax and AUC. Clearly, aqueous solubility has been identified as a barrier to the oral absorption of ATE. The information obtained from this study will facilitate further medicinal exploration on ATE.

Determination of naturally occurring resveratrol analog trans-4,4'-dihydroxystilbene in rat plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study.

trans-4,4'-Dihydroxystilbene (DHS) is a naturally occurring resveratrol analog that displayed promising anti-cancer activities in pre-clinical studies. To further probe its therapeutic potential, a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the measurement of DHS in rat plasma using electrospray ionization and multiple reaction monitoring in its negative ion mode. This analytical method demonstrated excellent linearity (R(2) > 0.99), selectivity, sensitivity (with a lower limit of quantification of 2.0 ng/mL), accuracy (both intra- and inter-day analytical recovery within 100 ± 15%) and precision (both intra- and inter-day relative standard deviation within 10%). The pharmacokinetic profiles of DHS were subsequently assessed in Sprague-Dawley rats. Following intravenous injection (4 mg/kg), DHS had a moderate apparent volume of distribution of the central compartment (V(c) = 887 ± 297 mL/kg), clearance (Cl = 44.7 ± 5.1 mL/min/kg) and a relatively short mean transit time (MTT = 24.1 ± 8.8 min). When it was given as an oral suspension (10 mg/kg), DHS was absorbed slowly (t max 180 or 300 min) with very limited plasma exposure and absolute oral bioavailability (F = 2.22 ± 0.72%). On the other hand, when DHS was fully solubilized by hydroxypropyl-ß-cyclodextrin, it was absorbed rapidly (t(max) 30 or 45 min) with more than 15-fold increase in maximal plasma concentration (C(max)), plasma exposure (AUC(0→last)) and bioavailability (F = 36.3 ± 4.8%). Statistical comparison provided clear evidence that DHS was better than resveratrol from the perspective of pharmacokinetics. In conclusion, further explorations of DHS as an anti-cancer agent are warranted.