Drug Metabolism and Pharmacokinetics

Diosbulbin B (DIOB) has been reported to cause serious liver injury. However, in traditional medicine, DIOB-containing herbs are highly safe in combination with ferulic acid (FA)-containing herbs, suggesting potential neutralizing effect of FA on the toxicity of DIOB. DIOB can be metabolized to generate reactive metabolites (RMs), which can covalently bind to proteins and lead to hepatoxicity. In the present study, the quantitative method was firstly established for investigating the correlation between DIOB RM-protein adducts (DRPAs) and hepatotoxicity...

The urinary metabolic ratio of 6β-hydroxydexamethasone to dexamethasone reportedly acts as a noninvasive marker for human cytochrome P450 (P450) 3A4/5, which is induced by rifampicin in humanized-liver mice. In the current study, the pharmacokinetics of dexamethasone in humanized-liver mice after intravenous administration (10 mg/kg) were investigated using azamulin (a time-dependent P450 3A4/5 inhibitor). After intravenous dexamethasone administration, significant differences were observed in the time-dependent plasma and 24-h urinary concentrations of 6β-hydroxydexamethasone between untreated humanized-liver mice and humanized-liver mice treated with azamulin (daily oral doses of 15 mg/kg for 3 days)...

This article reviews the impacts on the in vivo prediction of oral bioavailability (BA) and bioequivalence (BE) based on Biopharmaceutical classification systems (BCS) by the food-drug interaction (food effect) and the gastrointestinal (GI) environmental change. Various in vitro and in silico predictive methodologies have been used to expect the BA and BE of the test oral formulation. Food intake changes the GI physiology and environment, which affect oral drug absorption and its BE evaluation. Even though the pHs and bile acids in the GI tract would have significant influence on drug dissolution and, hence, oral drug absorption, those impacts largely depend on the physicochemical properties of oral medicine, active pharmaceutical ingredients (APIs)...

Black ginger is used as an herbal medicine for self-care and health promotion. Black ginger extract has been shown to alter the function of transporters in several cell types. This study demonstrates the interaction between the extract and 5,7-dimethoxyflavone (DMF) on drug efflux mediated by breast cancer resistance proteins (BCRP) and P-glycoprotein (P-gp) in Caco-2 cells and heterologous cell systems [Madin-Darby canine kidney type II (MDCKII) stably transfected with human BCRP (MDCKII/BCRP) or human P-gp (MDCKII/P-gp)]...

Understanding the physiological effects of food ingredients on bodily functions is crucial for the development of foods for specified health use (FoSHU) and functional foods. To investigate this, intestinal epithelial cells (IECs) have been widely studied as they are most frequently exposed to the highest concentrations of food ingredients. Among the various functions of IECs, in this review, we have discussed glucose transporters and their involvement in preventing metabolic syndromes such as diabetes. Phytochemicals are also discussed, as they significantly inhibit glucose and fructose absorption via sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 5 (GLUT5), respectively...

Herein, we aimed to determine the significance of drug interactions (DIs) between ritonavir and direct oral anticoagulants (DOACs) and identify the involved cytochrome P450 (CYP) isoenzymes. Using an in vitro cocktail method with human liver microsomes (HLM), we observed that ritonavir strongly inhibited CYPs in the following order: CYP3A, CYP2C8, CYP2D6, CYP2C9, CYP2C19, CYP2B6, and CYP2J2 (IC50 : 0.023-6.79 μM). The degree of CYP2J2 inhibition was inconclusive, given the substantial discrepancy between the HLM and human expression system...

Caco-2 cells are widely used as an in vitro intestinal model. However, the expression levels of the drug-metabolizing enzymes CYP3A4 and UGT1A1 are lower in these cells than in intestinal cells. Furthermore, the majority of prodrugs in use today are ester-containing, and carboxylesterase (CES) 1 and CES2 are among the enzymes that process the prodrugs into drugs. In the human small intestine, CES1 is hardly expressed while CES2 is highly expressed, but the CES expression pattern in Caco-2 cells is the opposite...

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9-17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption...

Antibiotic administration affects pharmacokinetics through changes in the intestinal microbiota, and bile acids are involved in this regulation. The purpose of the present study was to clarify the effect of different periods of antibiotic administration on the hepatic bile acid profile and expression of pharmacokinetic-related proteins in mouse liver, kidney, and brain capillaries. Vancomycin and polymyxin B were orally administered to mice for either 5- or 25-days. The hepatic bile acid profile of the 25-day treatment group was distinct...

OBJECTIVES: To investigate how cyclosporine A, a nonspecific efflux-pump blocker, affects the plasma concentrations and oral bioavailability of tigecycline, oxytetracycline, chlortetracycline, doxycycline, minocycline, and tetracycline. METHODS: Broiler chickens were used as an animal model. The tetracyclines (10 mg/kg BW) were administered intravenously, orally, and orally with cyclosporine A (50 mg/kg BW; administration: oral or intravenous). After administration, plasma samples were taken, and their concentrations of tetracyclines were measured using high-performance liquid chromatography coupled with tandem mass spectrometry...

Drug absorption from drug products may be affected by pharmaceutical excipients and/or food additives through different mechanisms. Chitosan is a recognized nutraceutical, with potential as an excipient due to its permeability enhancer properties. While chitosan properties have been evaluated in in vitro and pre-clinical models, studies in humans are scarce. Unexpectedly, a controlled clinical trial showed chitosan actually reduced acyclovir bioavailability. The effect seems to be related to an interaction with gastrointestinal mucus that prevents further absorption, although more in depth research is needed to unravel the mechanism...

A ligand-accessible space in the CYP2C8 active site was reconstituted as a fused grid-based Template∗ with the use of structural data of the ligands. An evaluation system of CYP2C8-mediated metabolism has been developed on Template with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C8 and its ligands through the simultaneous plural-contact with Rear-wall of Template...

Phenotype-gene analyses and the increasing availability of mega-databases have revealed the impaired human flavin-containing monooxygenase 3 (FMO3) variants associated with the metabolic disorder trimethylaminuria. In this study, a novel compound variant of FMO3, p.[(Val58Ile; Tyr229His)], was identified in a 1-year-old Japanese girl who had impaired FMO3 metabolic capacity (70%) in terms of urinary trimethylamine N-oxide excretion levels divided by total levels of trimethylamine and its N-oxide. One cousin in the family had the same p...

Food ingestion affects the oral absorption of many drugs in humans. In this review article, we summarize the physiological factors in the gastrointestinal (GI) tract that affect the in vivo performance of orally administered solid dosage forms in fasted and fed states in humans. In particular, we discuss the effects of food ingestion on fluid characteristics (pH, bile concentration, and volume) in the stomach and small intestine, GI transit of water and dosage forms, and microbiota. Additionally, case examples of food effects on GI physiology and subsequent changes in oral drug absorption are provided...

P-glycoprotein (P-gp) expression in lymphocytes is variable and 2-fold higher in rheumatoid arthritis (RA) patients with treatment resistance than in healthy subjects. To date the information on P-gp-mediated drug interaction in lymphocyte is limited. We analyzed the importance on P-gp in lymphocytes using peripheral blood mononuclear cells (PBMCs) together with K562, K562/Adr, and K562/Vin cells, which have various P-gp levels, as cell models, and dexamethasone, nintedanib and apafant as weak to good P-gp substrates...

Drug interactions between atorvastatin and cytochrome P450 (P450) 3A substrates/inhibitors lead to an increased incidence of skeletal muscle or hepatic toxicity. However, in this survey, among 483 Japanese subjects administered atorvastatin alone, more than half (258) experienced statin intolerance and were unable to continue using the drug. Although many factors underly atorvastatin toxicity, the intrinsic clearance rate might be a contributing causal factor. The impaired P450 3A4 p.Thr185Ser variant, CYP3A4∗16 (rs12721627), has been identified in East Asians with an allele frequency of 2...

The mouse cytochrome P450 1A2 (Cyp1a2) gene is one of the constitutive androstane receptor (CAR, NR1I3) activator-inducible genes, and the regions involved in induction were examined herein. A reporter gene assay indicated the involvement of the -0.2-kb region in the induction of transcriptional activation by the mouse CAR agonist ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). Some putative nuclear receptor-binding elements were identified in this region, and mutations in the elements located at -160/-155 or -153/-148 abolished this induction...

Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study...

Dabigatran etexilate (DABE), an oral anticoagulant prodrug, is nearly completely metabolized to the dabigatran (DAB) active metabolite by carboxylesterase-1 (CES1) and carboxylesterase-2 (CES2). The high interpatient variation in DAB plasma concentrations, coupled with its low therapeutic index, emphasizes the need to understand how CES1 and CES2 impact active metabolite formation. Previous work focused on CES1 enzyme activity but the contributions of CES2 remain unclear. The purpose of this study was to determine how CES2 activity influences DAB active metabolite formation...

A ligand-accessible space in the CYP2C19 active site was reconstituted as a fused grid-based Template with the use of structural data of the ligands. An evaluation system of CYP2C19-mediated metabolism has been developed on Template with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental results suggested a unified way of the interaction of CYP2C19 and its ligands through the simultaneous plural-contact with Rear-wall of Template...