The bioavailability of two altretamine preparations was studied in a randomized cross-over design. The two preparations were compared with a third in a parallel design. Dissolution differences between the preparations were observed, which could give rise to differences in bioavailability caused by the extensive first-pass effect of altretamine. Thein vivo data showed a trend to differences in bioavailability.

Purpose

To analyze the effect of liver steatosis and obesity on pharmacokinetic profile of two structurally-related liver-selective NO-donors — V-PYRRO/NO and V-PROLI/NO.

Methods

C57BL/6 mice were fed control or high-fat diet for 15 weeks to induced liver steatosis and obesity (HFD mice). Pharmacokinetics and renal elimination studies were conducted in vivo following iv dosing of V-PYRRO/NO and V-PROLI/NO (0.03 mmol/kg). Hepatic clearance was evaluated ex vivo in the isolated perfused mice liver and in vitro with the use of liver microsomes.

Results

V-PYRRO/NO and V-PROLI/NO, despite similar structure, displayed different pharmacokinetic properties. V-PYRRO/NO was uptaken and metabolized by the liver, while V-PROLI/NO was eliminated unchanged with urine. In HFD mice, despite increased CYP450 metabolism of V-PYRRO/NO the elimination rate was slower most likely due to the impairment of hepatic microcirculation caused by liver fat accumulation. In turn, in HFD mice renal clearence of V-PROLI/NO was accelerated and volume of distribution was increased most likely due to additional intracellular water in HFD mice.

Conclusions

The pharmacokinetics of V-PROLI/NO, the novel proline-based analog of V-PYRRO/NO with additional single carboxylic acid moiety, attached to the molecule of V-PYRRO/NO to improve the water solubility, was differently affected by liver steatosis and obesity as compared with the parent compound V-PYRRO/NO.

A specific and sensitive liquid chromatography-electrospray ionization tandem mass spectrometry method was developed for the determination of zolmitriptan and N-desmethylzolmitriptan in human plasma. The analytes and the internal standard (IS) paroxetine were extracted by liquid–liquid extraction with a mixture of saturated ethyl acetate:dichloromethane (4:1) and were separated using an isocratic mobile phase on a XTerra RP18 column. The mobile phase used was acetonitrile: 5 mM ammonium acetate: formic acid (50:50:0.053, v/v/v). Zolmitriptan and N-desmethylzolmitriptan in a range of 0.25–20 ng mL⁻¹ were easily quantified. The validated method can be applied to pharmacokinetic and bioequivalence studies.

Hwang-Ryun-Hae-Dok-Tang (HT; a standardized herbal formula consisting of extracts from Coptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus) was reported to modulate a function of multidrug resistance associated protein 2 (Mrp2) in vitro. The aim of this study was to assess the in vivo pharmacokinetic interactions between HT and phenolsulfonphthalein (PSP), a typical model Mrp2 substrate eliminated via bile through Mrp2 in rats. Rats received intravenous PSP (0.8 mg/kg) followed by either a single oral dose of HT (0.42 g/kg) or multiple oral doses of HT (0.42 g/kg for 7 days). The effect of HT treatment was also investigated at a steady-state after intravenous PSP infusion. In contrast to previous in vitro results, in this study, we found that the HT-treated and control groups did not show any significant difference in the plasma PSP concentration and pharmacokinetic parameters, including area under the plasma concentration-time curve (AUC; control: 118 ± 19, single dose: 116 ± 40, and multiple dose: 137 ± 4, in mg/(min·mL)) and biliary clearance (control: 3.15 ± 0.69, single dose: 2.59 ± 1.11, and multiple dose: 2.53 ± 0.65, in mL/(min·kg)). However, cyclosporine A (5 mg/kg, an inhibitor of Mrp2) significantly decreased the AUC and biliary clearance of PSP. The steady-state plasma concentration and biliary clearance of PSP-were also similar between the groups. Taken together, our results suggest that HT may not be affected by Mrp2-mediated herb-drug interaction in vivo.

The objectives of the simulation study were to evaluate the impact of BQL data on pharmacokinetic (PK) parameter estimates when the incidence of BQL data is low (e.g. ≤10%), and to compare the performance of commonly used modeling methods for handling BQL data such as data exclusion (M1) and likelihood-based method (M3). Simulations were performed by adapting the method of a recent publication by Ahn et al. (J Phamacokinet Pharmacodyn 35(4):401–421, 2008). The BQL data in the terminal elimination phase were created at frequencies of 1, 2.5, 5, 7.5, and 10% based on a one- and a two-compartment model. The impact of BQL data on model parameter estimates was evaluated based on bias and imprecision. The simulations demonstrated that for the one-compartment model, the impact of ignoring the low percentages of BQL data (≤10%) in the elimination phase was minimal. For the two-compartment model, when the BQL incidence was less than 5%, omission of the BQL data generally did not inflate the bias in the fixed-effect parameters, whereas more pronounced bias in the estimates of inter-individual variability (IIV) was observed. The BQL data in the elimination phase had the greatest impact on the volume of distribution estimate of the peripheral compartment of the two-compartment model. The M3 method generally provided better parameter estimates for both PK models than the M1 method. However, the advantages of the M3 over the M1 method varied depending on different BQL censoring levels, PK models and parameters. As the BQL percentages decreased, the relative gain of the M3 method based on more complex likelihood approaches diminished when compared to the M1 method. Therefore, it is important to balance the trade-off between model complexity and relative gain in model improvement when the incidence of BQL data is low. Understanding the model structure and the distribution of BQL data (percentage and location of BQL data) allows selection of an appropriate and effective modeling approach for handling low percentages of BQL data.

Background

Effective immunosuppression through optimization of trough levels tacrolimus reduces post-transplant mortality rate in liver transplant cases.

Methods

Meta-analysis was carried out to evaluate how donor/recipient CYP3A5 (n = 678) and recipient ABCB1 (n = 318) genotypes influence tacrolimus pharmacokinetics till one-month of transplantation.

Results

The donor CYP3A5*3/*3 genotype exhibited higher concentration/dose (C/D) ratio of tacrolimus in week 1 (mean difference: 65.04, 95% CI: 15.30–114.79 ng/ml/mg/kg), week 2 (mean difference: 21.7, 95% CI: 12.6–30.9 ng/ml/mg/kg) and week 4 (mean difference: 43.28, 95% CI: 17.09 — 69.49 ng/ml/mg/kg) compared to *1/*1 and *1/*3 genotypes. The recipient CYP3A5 *3/*3 genotype did not showed significant difference in tacrolimus C/D ratio in week 1 compared to other two genotypes. However, week 2 (mean difference: 44.16, 95% CI: 3.68–84.65 ng/ml/mg/kg) and week 4 (mean difference: 43.74, 95% CI: 12.50–75.00 ng/ml/mg/kg) availability was higher in *3/*3 mutant recipients. However, the recipient ABCB1 3435 C > T polymorphism has no significant influence on tacrolimus pharmacokinetics till one month of transplant.

Conclusions

The donor and recipient CYP3A5*3 polymorphism influences tacrolimus pharmacokinetics in the first month post-transplantation, whereas the association with recipient ABCB1 3435 C > T is inconclusive.

Male Sprague-Dawley rats deprived of water for 72 h (a rat model of dehydration) showed no change in protein expression of the hepatic microsomal cytochrome P450 (CYP) 1A2, 2B1/2, 2C11, or 3A1/2, but an increase in protein expression (3-fold) and mRNA level (2.6-fold) of CYP2E1. Glucose feeding instead of food normalized CYP2E1 protein expression during dehydration. Here, we review how dehydration can change the pharmacokinetics of drugs reported in the literature via changing CYP isozyme levels. We also discuss how dehydration changes the pharmacokinetics of drugs that are metabolized via renal DHP-I, or are mainly excreted in the urine and bile, and form conjugates.

Enantioselective pharmacokinetics and absorption of eflornithine in the rat was investigated using population pharmacokinetic modeling and a modified deconvolution method. Bidirectional permeability of l- and d-eflornithine was investigated in Caco-2 cells. The rat was administered racemic eflornithine hydrochloride as a single oral dose [40–3,000 mg/kg bodyweight (BW)] or intravenously (IV) (100–2,700 mg/kg BW infused over 60–400 min). Serial arterial blood samples were collected and l- and d-eflornithine were quantitated with a previously published chiral bioanalysis method. The D:L concentration ratio was determined in rat faeces. Intravenous l-and d-eflornithine plasma concentration–time data was analyzed using population pharmacokinetic modeling and described with a 3-compartment pharmacokinetic model with saturable binding to one of the peripheral compartments. Oral plasma concentration–time data was analyzed using a modified deconvolution method accounting for nonlinearities in the eflornithine pharmacokinetics. Clearance was similar for both enantiomers (3.36 and 3.09 mL/min). Oral bioavailability was estimated by deconvolution at 30 and 59 % for l- and d-eflornithine. The D:L concentration ratio in feces was 0.49 and the Caco-2 cell permeability was similar for both enantiomers (6–10 × 10⁻⁸ cm/s) with no evident involvement of active transport or efflux. The results presented here suggest that the difference in the bioavailability between eflornithine enantiomers is caused by a stereoselective difference in extent rather than rate of absorption. The presented modified deconvolution method made it possible to account for the non-linear component in the suggested three-compartment pharmacokinetic model thus rapidly estimating eflornithine oral bioavailability.

The herbal medicament derived from the lipid soluble fraction obtained from Curcuma longa L. (Zingiberaceae) has shown potential neuroprotective activity in disorders like stroke. HM has been standardized with three biomarkers: ar-turmerone, α/β-turmerone and curlone, major bisabolane sesquiterpenes of turmeric oil. Development of a biaonalytical method for these sesquiterpenes was initiated to characterize its preclinical pharmacokinetics in rabbits to accelerate its development as a potential candidate for vascular complications. Since, the compounds are structurally and chemically very similar, gradient elution was utilized on a C-18 reversed phase column with a mobile phase comprising of acetonitrile and deionised water. The UV detector was set at wavelengths 240 and 270 nm. The sample clean-up was performed by protein precipitation with acetonitrile. The method was reasonably sensitive with limits of quantitation (LOQ) of 0.098 μg mL⁻¹ in plasma for all the analytes. Accuracy and precision were within the acceptable limits, as indicated by relative standard deviation (% RSD) varying from 1.3 to 13.6% and bias values ranging from −5.5 to 10.3%, respectively. Moreover, the analytes were stable in plasma even after three freeze-thaw cycles. The method was applied to generate preliminary pharmacokinetics of turmeric oil in rabbits after intravenous administration.

Docetaxel is a P-glycoprotein (P-gp) substrate and metabolized via cytochrome P450 (CYP) 3A subfamily in rats. Morin is an inhibitor of both CYPs and P-gp. Hence, the effects of morin on the intravenous and oral pharmacokinetics of docetaxel were investigated using 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor rats (DMBA rats) as an animal model of human breast cancer. Docetaxel was administered intravenously (4 mg/kg) and orally (20 mg/kg) without and with morin (15 mg/kg) in DMBA rats. After the intravenous administration of docetaxel in control and DMBA rats with and without morin, the values of non-renal clearance and area under the plasma concentration-time (AUC) for docetaxel were comparable. Morin did not increase AUC or the absolute oral bioavailability (F) for docetaxel after the oral administration of docetaxel in control and DMBA rats with and without morin. The inhibition of hepatic and intestinal metabolism of docetaxel by morin and/or DMBA and the effect of intestinal P-gp inhibition by morin on the pharmacokinetics of docetaxel did not seem to be considerable in DMBA-induced mammary tumor rats.