Effects of Nonalcoholic Fatty Liver Disease on Hepatic CYP2B1 and in Vivo Bupropion Disposition in Rats Fed a High-Fat or Methionine/Choline-Deficient Diet.

Nonalcoholic fatty liver disease (NAFLD) refers to hepatic pathologies, including simple fatty liver (SFL), nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, that may progress to hepatocellular carcinoma. These liver disease states may affect the activity and expression levels of drug-metabolizing enzymes, potentially resulting in an alteration in the pharmacokinetics, therapeutic efficacy, and safety of drugs. This study investigated the hepatic cytochrome P450 (CYP) 2B1-modulating effect of a specific NAFLD state in dietary rat models. Sprague-Dawley rats were given a methionine/choline-deficient (MCD) or high-fat (HF) diet to induce NASH and SFL, respectively. The induction of these disease states was confirmed by plasma chemistry and liver histological analysis. Both the protein and mRNA levels of hepatic CYP2B1 were considerably reduced in MCD diet-fed rats; however, they were similar between the HF diet-fed and control rats. Consistently, the enzyme-kinetic and pharmacokinetic parameters for CYP2B1-mediated bupropion metabolism were considerably reduced in MCD diet-fed rats; however, they were also similar between the HF diet-fed and control rats. These results may promote a better understanding of the influence of NAFLD on CYP2B1-mediated metabolism, which could have important implications for the safety and pharmacokinetics of drug substrates for the CYP2B subfamily in patients with NAFLD.

Application of montmorillonite in bentonite as a pharmaceutical excipient in drug delivery systems.

Montmorillonite is a multifunctional clay mineral and a major component of bentonite. Montmorillonite has been used in various industrial and pharmaceutical fields due to its unique characteristics, which include swelling and adsorption. The high adsorption capacity of montmorillonite contributes to increase drug entrapment and sustained-release of drugs. Montmorillonite generally sustains drug release in many formulations by strongly adsorbing to the drug. In addition, montmorillonite enhances the dissolution rate and bioavailability of hydrophobic drugs. Moreover, montmorillonite was applied to form composites with other polymer-based delivery systems. Thus, montmorillonite could be applied to formulate diverse drug delivery systems to control and/or improve the pharmaceutical properties of drugs, including solubility, dissolution rate, and absorption. In this review, perspectives of applying montmorillonite as a pharmaceutical excipient in drug delivery systems are discussed.

Use of injectable drugs with oral-formulation alternatives for outpatients in South Korea.

This study analyzed the use of injectable drugs with oral-formulation alternatives in the outpatient setting in South Korea. We conducted a retrospective cross-sectional data analysis using 2008 National Health Insurance claims data. All active ingredients were categorized into dual-formulation ingredients (DFIs) and single formulation ingredients (SFIs), and were identified by the type of healthcare service provider (HSP) and anatomical therapeutic chemical (ATC) group. 14.6 % (102/701) of total drugs were extracted as DFIs at about the same rate as that for drugs in the World Health Organization database (14.45 %), showing similar patterns by ATC group. The rate of injectable drug use varied more substantially for DFIs (range 0.94-4.54 %) than for SFIs (range 0.27-1.12 %) by the type of HSP. For DFIs, the highest proportion of injectable drug use was observed in group H (all hormonal preparations, 22.74 %) and group M (anti-inflammatory and anti-rheumatic preparations, 10.23 %) among ATC groups. The proportion of injectable drug use was higher in clinics and small hospitals than in tertiary hospitals and general hospitals where patients with more severe cases tend to visit. The results imply the potentially inappropriate or excessive use of injectable drugs and suggest the need to develop standard guidelines for injectable drug use and strategies to promote high-quality healthcare including education on rational prescribing.

Population pharmacokinetic-pharmacogenetic model of tacrolimus in the early period after kidney transplantation.

As tacrolimus has a rather narrow therapeutic range and high individual variability in its pharmacokinetics, it is important to determine the cause of the variation in tacrolimus pharmacokinetics. The purpose of this study was to establish a population pharmacokinetic-pharmacogenetic model of tacrolimus and identify covariates that affect pharmacokinetic parameters to prevent fluctuations in the tacrolimus trough concentration during the early period after transplantation. Data from 1501 trough concentrations and 417 densely collected concentrations were compiled from 122 patients who were on post-operative days 10-20 and analysed with a nonlinear mixed-effect model. The first-order conditional estimation (FOCE) with interaction method was used to fit the model using the NONMEM program. Clinical/laboratory data were also collected for the same period, and CYP3A5 and ABCB1 genotypes were analysed for use in modelling from all included patients. An empirical Bayesian approach was used to estimate individual pharmacokinetic profiles. A one-compartment model with first absorption and elimination and lag time best described the data. The estimated population mean of clearance (CL/F), volume of distribution (V/F) and absorption rate (Ka ) were 21.9 L/hr, 205 L, and 3.43/hr, respectively, and the lag time was fixed at 0.25 hr. Clearance increased with days after transplantation and decreased with CYP3A5*3/*3 about 18.4% compared with CYP3A5*1 carriers (p < 0.001). A population pharmacokinetic model was developed for tacrolimus in early post-kidney transplantation recipients to identify covariates that affect tacrolimus pharmacokinetics. Post-operative days and CYP3A5 genotype were confirmed as critical factors of tacrolimus pharmacokinetics.