Kinetics of the inhibition of CYP3A4 and CYP2C19 activity by jabara juice and identification of the responsible inhibitory components.

Some citrus fruits are known to cause clinically significant drug interactions by inhibiting intestinal cytochrome P450 (CYP) enzymes. This in vitro study aimed to investigate the kinetics of the inhibition of CYP3A4 and CYP2C19 by the juice of jabara, a Japanese citrus fruit that does not contain furanocoumarins such as 6',7'-dihydroxybergamottin, and to identify the inhibitory compound(s). CYP3A4 and CYP2C19 activity levels were determined in vitro using recombinant CYP preparations and their respective substrates.

The Effects of N-Glycosylation on the Expression and Transport Activity of OATP1A2 and OATP2B1.

Organic anion transporting polypeptide (OATP)1A2 and OATP2B1 have potential N-glycosylation sites, but their influence remains unclear. This study aimed to identify the N-glycosylation sites of OATP1A2/2B1 and investigate their impact on the expression and function of OATP1A2/2B1. Human embryonic kidney cells expressing OATP1A2 or OATP2B1 (HEK293-OATP1A2/2B1) were exposed to tunicamycin, an N-glycosylation inhibitor, and a plasma membrane fraction (PMF) Western blot assay and an estrone 3-sulfate (E3S) uptake study were conducted.

The Effects of Jabara Juice on the Intestinal Permeation of Fexofenadine.

Jabara juice and its component narirutin inhibit the activity of organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1, which are considered to play significant roles in the intestinal absorption of fexofenadine. In this study, we investigated the effects of jabara juice on the intestinal absorption of fexofenadine in mice and the inhibitory effects of jabara juice and narirutin on the permeation of fexofenadine using Caco-2 cell monolayers and LLC-GA5-COL300 cell monolayers. In the in vivo study, the area under the plasma concentration-time curve (AUC) of fexofenadine in mice was increased 1.

The influence of temperature on the metabolic activity of CYP2C9, CYP2C19, and CYP3A4 genetic variants .

1. Temperature is considered to affect the activity of drug-metabolizing enzymes; however, no previous studies have compared temperature dependency among cytochrome P450 genetic variants. This study aimed to analyse warfarin 7-hydroxylation by CYP2C9 variants; omeprazole 5-hydroxylation by CYP2C19 variants; and midazolam 1-hydroxylation by CYP3A4 variants at 34 °C, 37 °C, and 40 °C.

Irinotecan-induced gastrointestinal damage alters the expression of peptide transporter 1 and absorption of cephalexin in rats.

Irinotecan causes severe gastrointestinal damage, which may affect the expression of intestinal transporters. However, neither the expression of peptide transporter 1 (Pept1) nor the pharmacokinetics of Pept1 substrate drugs has been investigated under irinotecan-induced gastrointestinal damage. Therefore, the present study quantitatively investigated the effects of irinotecan-induced gastrointestinal damage on the intestinal expression of Pept1 and absorption of cephalexin (CEX), a typical Pept1 substrate, in rats.

Comparison of the transport kinetics of fexofenadine and its pH dependency among OATP1A2 genetic variants.

Little is known about the influence of non-synonymous genetic variations in the organic anion-transporting polypeptide (OATP) 1A2 on the transport kinetics of its substrate fexofenadine. Moreover, the pH-dependency of fexofenadine uptake also remains unclear. This study aimed to evaluate the effects of genetic variants (Ile13Thr, Asn128Tyr, Glu172Asp, Ala187Thr, and Thr668Ser) on the OATP1A2-mediated uptake of fexofenadine at pH 6.

Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants.

Non-synonymous genetic variants of organic anion-transporting polypeptide (OATP) 1A2 with altered transport activity have been identified. Naringin and narirutin, which are found in grapefruit, and their aglycon naringenin inhibit OATP1A2. However, their inhibitory effects on OATP1A2 variants have not been investigated, nor has the influence of their molecular structure, such as the number of sugar moieties, on their inhibitory potency.

Mechanistic bottom-up estimation of passive drug absorption from the gastrointestinal tract: Comparison among primary cultured human intestinal cells, Caco-2 cells, artificial membrane, and animal scale-up.

Objective: The fraction of drug absorbed (Fa) from the intestine is an important parameter to characterize the pharmacokinetics of a drug. We aimed to search for an experimental system that provides the best parameters for estimating the effective permeability (P) used for the bottom-up prediction of Fa.

Materials And Methods: The absorption kinetics of 12 passively absorbed drugs were simulated by a compartment absorption transit (CAT) model using absorption parameters from four different experimental systems: human intestinal epithelial cell (HIEC) monolayer, Caco-2 monolayer, parallel artificial membrane permeability assay (PAMPA), and in situ rat intestinal perfusion.

Inhibitory Effects of Cranberry Juice and Its Components on Intestinal OATP1A2 and OATP2B1: Identification of Avicularin as a Novel Inhibitor.

Organic anion-transporting polypeptide (OATP) 1A2 and OATP2B1 mediate the intestinal absorption of drugs. This study aimed to identify fruit juices or fruit juice components that inhibit OATPs and assess the risk of associated food-drug interactions. Inhibitory potency was assessed by examining the uptake of [H]estrone 3-sulfate and [H]fexofenadine into HEK293 cells expressing OATP1A2 or OATP2B1.

Evaluation of hepatic CYP3A enzyme activity using endogenous markers in lung cancer patients treated with cisplatin, dexamethasone, and aprepitant.

Purpose: Aprepitant is used with dexamethasone and 5-HT receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression.

Analysis of inhibition kinetics of three beverage ingredients, bergamottin, dihydroxybergamottin and resveratrol, on CYP2C9 activity.

Some grapefruit juice (GFJ) ingredients and resveratrol, a fruit-derived phytoalexin, are known to inhibit cytochrome P450 (CYP) 2C9. However, their inhibition modes and detailed inhibition kinetics remain undetermined. This study aimed to investigate the inhibitory effects of two GFJ ingredients, bergamottin (BG) and dihydroxybergamottin (DHB), and resveratrol on CYP2C9 activity in vitro.

Dual kinetics of OATP2B1: Inhibitory potency and pH-dependence of OATP2B1 inhibitors.

Organic anion transporting polypeptide (OATP) 2B1 is expressed in the intestine and liver, and OATP2B1-mediated transport of estrone 3-sulfate is pH-dependent and consists of: the high-affinity component (Hc) and low-affinity component (Lc). This study aimed to evaluate the influence of pH on the transport kinetics of each component, along with the inhibitory nature of ten OATP2B1 inhibitors. The Michaelis constants (K) were 4-fold and 1.

Time-dependent inhibition of CYP3A4-mediated midazolam metabolism by macrolide antibiotics in CYP3A4 genetic variants: Comparison with testosterone metabolism.

Objectives: The present study aimed to evaluate the effects of CYP3A4 genetic variation on the kinetics of mechanism-based inhibition (MBI) of both inhibitors using midazolam as a substrate for comparison with our previous study, as midazolam and testosterone have different binding sites.

Background: The genetic variation of cytochrome P450 (CYP) 3A4 affects MBI, expressed as the maximum inactivation rate constant () and the inhibitor concentration required to achieve half-maximal inactivation (). We previously showed, using testosterone as a substrate, that the MBI kinetics of erythromycin and clarithromycin differ among CYP3A4 variants.

Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage.

Background: Irinotecan (CPT-11) is clinically known to cause severe diarrhea and gastrointestinal damage. Recently, we have reported that CPT-11-induced gastrointestinal damage is associated with the upregulation of intestinal P-glycoprotein (P-gp) expression and decreased absorption of its substrate, dabigatran etexilate (DABE), using a rat model. However, the P-gp activity or its contribution to the decreased absorption remains unclear.

Estimation of absolute oral bioavailability without performing an intravenous clinical study.

The absolute oral bioavailability (BA) of drugs are yet to be determined, and intravenous pharmacokinetic studies are currently considered indispensable for determining the BA values of oral drugs. The aim of this study was to develop and validate a novel approach to estimating BA values without intravenous pharmacokinetic data. Based on the drug inclusion criteria, such as exhibiting a urinary recovery rate of (R) of ≥20% in a clinical study, 13 drugs were included in the present study, and pharmacokinetic data for them were collected from the literature.

Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants.

Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals inhibit CYP3A4 to cause clinically significant drug-drug interactions.

Exacerbation of atrioventricular block associated with concomitant use of amlodipine and aprepitant in a lung cancer patient: A case report.

Objective: To report a case of second-degree atrioventricular block associated with concomitant use of aprepitant and amlodipine.

Case: A 73-year-old man with lung cancer was treated with aprepitant for prophylactic use for the prevention of nausea and vomiting, concomitantly with cisplatin, gemcitabine, and an investigational drug (anti-epidermal growth factor receptor monoclonal antibody). He was diagnosed with first-degree atrioventricular block and was taking amlodipine for hypertension.

Citrus Fruit-Derived Flavanone Glycoside Narirutin is a Novel Potent Inhibitor of Organic Anion-Transporting Polypeptides.

Organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1 are expressed in the small intestine and are involved in drug absorption. We identified narirutin, which is present in grapefruit juice, as a novel OATP inhibitor. The citrus fruit jabara also contains high levels of narirutin; therefore, we investigated the inhibitory potency of jabara juice against OATPs.

Relative contributions of metabolic enzymes to systemic elimination can be estimated from clinical DDI studies: Validation using an in silico approach.

Objective: The contribution ratios (CR) of metabolic enzymes to the systemic clearance of a drug can be estimated from in vitro studies. Another feasible approach is to calculate them based on the increase in the area under the time-concentration curve (AUC) caused by the co-administration of a potent and selective inhibitor in a clinical drug-drug interaction (DDI) study. However, some factors, such as the inhibitory potency of the inhibitor and the inhibition of first-pass metabolism, might affect the estimation of CR based on clinical DDI studies.

Correction to: Novel method to estimate the appropriate dosing interval for activated charcoal to avoid interaction with other drugs.

Figure 3 image was inadvertently removed from the original article. The original article has been corrected.

Profile of the inhibitory effects of gefitinib on CYP2D6 variants in vitro.

Objective: CYP2D6 is a highly polymorphic metabolic enzyme with more than 100 genetic variants, some of which are associated with significantly altered enzyme activity, such as CYP2D6.2 (ArgCys, SerThr), CYP2D6.10 (ProSer, SerThr), and CYP2D6.

Novel method to estimate the appropriate dosing interval for activated charcoal to avoid interaction with other drugs.

Purpose: Activated charcoal is known to adsorb a variety of drugs concomitantly administered and reduce their intestinal absorption, and separating the dosing is considered a practical approach to avoid this drug interaction. The aim of the present study was to develop and validate a simple method to estimate the sufficient dosing interval to avoid drug interaction using the pharmacokinetic profile of the subject drugs administered alone and the amplitude of interaction upon simultaneous administration with activated charcoal.

Methods: For each subject drug, the pharmacokinetic profile and the amplitude of interaction, as assessed by AUCR (the ratio of area under the plasma concentration-time curve (AUC) in the presence of activated charcoal to that in its absence), were collected from previous reports.

pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2.

Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS.

Irinotecan-induced gastrointestinal damage impairs the absorption of dabigatran etexilate.

Irinotecan causes serious gastrointestinal damage. Dabigatran etexilate (DABE), an oral anticoagulant and substrate of P-glycoprotein (P-gp), is poorly absorbed and exhibits low bioavailability in humans. The aim of this study was to evaluate the effects of irinotecan-induced gastrointestinal damage on the pharmacokinetics/pharmacodynamics (PK/PD) of DABE.