Estimation of the minimum permeability coefficient in rats for perfusion-limited tissue distribution in whole-body physiologically-based pharmacokinetics.

The objective of the current study was to determine the minimum permeability coefficient, P, needed for perfusion-limited distribution in PBPK. Two expanded kinetic models, containing both permeability and perfusion terms for the rate of tissue distribution, were considered: The resulting equations could be simplified to perfusion-limited distribution depending on tissue permeability. Integration plot analyses were carried out with theophylline in 11 typical tissues to determine their apparent distributional clearances and the model-dependent permeabilities of the tissues. Effective surface areas were calculated for 11 tissues from the tissue permeabilities of theophylline and its PAMPA P. Tissue permeabilities of other drugs were then estimated from their PAMPA P and the effective surface area of the tissues. The differences between the observed and predicted concentrations, as expressed by the sum of squared log differences with the present models were at least comparable to or less than the values obtained using the traditional perfusion-limited distribution model for 24 compounds with diverse PAMPA P values. These observations suggest that the use of a combination of the proposed models, PAMPA P and the effective surface area can be used to reasonably predict the pharmacokinetics of 22 out of 24 model compounds, and is potentially applicable to calculating the kinetics for other drugs. Assuming that the fractional distribution parameter of 80% of the perfusion rate is a reasonable threshold for perfusion-limited distribution in PBPK, our theoretical prediction indicates that the pharmacokinetics of drugs having an apparent PAMPA P of 1×10-6cm/s or more will follow the traditional perfusion-limited distribution in PBPK for major tissues in the body.

Quantification of EC-18, a synthetic monoacetyldiglyceride (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol), in rat and mouse plasma by liquid-chromatography/tandem mass spectrometry.

EC-18 (i.e., 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol), an active ingredient in Rockpid®, has been reported to be useful in controlling various types of inflammations, particularly those caused by neutropenia. Although this product was originally approved as a functional food in Korea, it is currently in phase II clinical trials for use in managing the severe chemotherapy-induced neutropenia in patients with advanced breast cancer who are receiving intermediate febrile neutropenia risk chemotherapy. The objective of this study was to develop a rapid, sensitive method for the determination of EC-18 in rat and mouse plasma and to evaluate the applicability of the assay in pharmacokinetic studies. EC-18 was extracted with MeOH from rat and mouse plasma samples, and the extract directly introduced onto an LC-MS/MS system. The analyte and EC-18-d3, an internal standard, were analyzed by multiple reaction monitoring (MRM) at m/z transitions of 635.4→355.4 for EC-18 and 638.4→338.4 for the internal standard, respectively. The lower limit of quantification (LLOQ) was determined at 50ng/mL, with an acceptable linearity in the range from 50 to 10,000ng/mL (r>0.999) for both matrices. Validation parameters such as accuracy, precision, dilution, recovery, matrix effects and stability were found to be within the acceptance criteria of the assay validation guidelines, indicating that the assay is applicable for estimating EC-18 in concentrations in the range examined. EC-18 was readily determined in plasma samples for periods of up to 8h following an intravenous bolus injection of 1mg/kg in rats and at 5mg/kg in mice, respectively, and up to 24h following the oral administration of 2000mg/kg in mice. The findings indicate that the current analytical method is applicable for pharmacokinetic studies of EC-18 in small animals.

Specific Inhibition of the Distribution of Lobeglitazone to the Liver by Atorvastatin in Rats: Evidence for a Rat Organic Anion Transporting Polypeptide 1B2-Mediated Interaction in Hepatic Transport.

Cytochrome P450 enzymes and human organic anion transporting polypeptide (OATP) 1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new peroxisome proliferator-activated receptor γ agonist. Atorvastatin (ATV), a substrate for CYP3A and human OATP1B1, is likely to be coadministered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was administered intravenously with ATV, the systemic clearance and volume of distribution at steady state for LB remained unchanged (2.67 ± 0.63 ml/min per kg and 289 ± 20 ml/kg, respectively), compared with that of LB without ATV (2.34 ± 0.37 ml/min per kg and 271 ± 20 ml/kg, respectively). Although the tissue-to-plasma partition coefficient (Kp) of LB was not affected by ATV in most major tissues, the liver Kp for LB was decreased by ATV coadministration. Steady-state liver Kp values for three levels of LB were significantly decreased as a result of ATV coadministration. LB uptake was inhibited by ATV in rat OATP1B2-overexpressing Madin-Darby canine kidney cells and in isolated rat hepatocytes in vitro. After incorporating the kinetic parameters for the in vitro studies into a physiologically based pharmacokinetics model, the characteristics of LB distribution to the liver were consistent with the findings of the in vivo study. It thus appears that the distribution of LB to the liver is mediated by the hepatic uptake of transporters such as rat OATP1B2, and carrier-mediated transport is involved in the liver-specific drug-drug interaction between LB and ATV in vivo.

Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats.

This study was performed to determine biopharmaceutical properties of lobeglitazone (LB), a novel thiazolidinedione-based activator of peroxisome proliferator-activated receptor gamma, in rats. In parallel artificial membrane permeability assay and Madin-Darby canine kidney (MDCK) cell permeability assays of LB, the activator was found to interact with multidrug-resistance protein 1 (MDR1) and OATP1B1. The concentration resulting in 50% inhibition value for LB in MDR1 expressing MDCK cells was approximately 12.5 ± 3.61 µM. LB had adequate stability (i.e., 56% remaining at 0.5 h) in rat liver microsomes. A cytochrome P450 (CYP) inhibitory potency study indicated that LB is primarily interacted with CYP1A2, 2C9, and 2C19. In rats, LB appeared to be readily absorbed after an oral administration (an absolute bioavailability of ∼95%). Following intravenous administration, LB exhibited linear pharmacokinetics in the dose range of 0.5-2 mg/kg. The primary distribution site was the liver but it was also distributed to heart, lungs, and fat tissue. The excretion of LB to the urine, bile, feces, and intestine was insignificant (i.e., <10% of the dose) in rats. These observations suggest that, despite the fact that it interacts with some drug transporters and metabolizing enzymes, the pharmacokinetics of LB were linear with a high oral bioavailability.