Xin-yi-san contains potent human CYP1A2 inhibitors and its combined use with theophylline in treatment increases adverse risks in patients.

Background: The Xin-yi-san herbal decoction (XYS) is commonly used to treat patients with allergic rhinitis in Taiwan. Theophylline is primarily oxidized with high affinity by human cytochrome P450 (CYP)1A2, and has a narrow therapeutic index.

Purpose: This study aimed to investigate the inhibition of human CYP1A2-catalyzed theophylline oxidation (THO) by XYS and its adverse effects in patients.

The role of partial area under the curve and maximum concentrations in assessing the bioequivalence of long-acting injectable formulation of exenatide_A sensitivity analysis.

To ensure therapeutic equivalence between the long-acting injectable (LAI) products, additional PK metrics other than C and AUC were considered necessary. However, regarding the selection of additional PK metrics for bioequivalence (BE) assessment of exenatide LAI, a discrepancy existed between EMA's and USFDA's product-specific guidance. The EMA recommends that both the maximum plasma concentration in the initial-release phase (C) and the extended-release phase (C) should be determined.

Nalbuphine-6-glucuronide is a potent analgesic with superior safety profiles by altering binding affinity and selectivity for mu-/kappa-opioid receptors.

Although nalbuphine, a semi-synthetic analgesic compound, is less potent than morphine in terms of alleviating severe pain, our recent findings have revealed that nalbuphine-6-glucuronide (N6G), one of the glucuronide metabolites of nalbuphine, promotes a significantly more robust analgesic effect than its parent drug. Nevertheless, despite these promising observations, the precise mechanisms underlying the analgesic effects of nalbuphine glucuronides have yet to be determined. In this study, we aim to elucidate the mechanisms associated with the analgesic effects of nalbuphine glucuronides.

Identification of the perpetrator imperatorin in Xin-yi-san-theophylline interaction: observed and predicted herb-drug interaction in rats.

Objectives: Theophylline is a bronchodilator with a narrow therapeutic index and primarily metabolised by cytochrome P450 (CYP) 1A2. Xin-yi-san (XYS) is a herbal formula frequently used to ameliorate nasal inflammation. This study aimed to investigate the effects of XYS and its ingredient, imperatorin, on theophylline pharmacokinetics in rats.

3,4-Desaturation of retinoic acid by cytochrome P450 27C1 prevents P450-mediated catabolism.

Cytochrome P450 (P450, CYP) 27C1 is expressed in human skin and catalyzes the 3,4-desaturation of retinoids. The enzyme has a relatively high specificity constant (k/K), and ∼¼ of the retinoids in human skin are in the desaturated form but their function is unknown. 3,4-Dehydroretinoic acid (also didehydroretinoic acid, ddRA) has similar affinity as all-trans retinoic acid (atRA) for retinoid X and retinoic acid receptors (RXRs/RAR).

Metabolism-involved drug interactions with traditional Chinese medicines in cardiovascular diseases.

Herbal medicines have been widely used for the past millennia. Traditional Chinese medicine (TCM) is a major modality in Chinese medical care and has garnered global attention owing to its pharmacological effects and multi-targeted actions. The increased incidence of sequential or concurrent use of herbs and drugs in patients forces us to consider herb-drug interactions (HDIs) in this modern era.

Evidence of the need for modified well-stirred model in vitro to in vivo extrapolation.

In vitro to in vivo extrapolation (IVIVE), an approach for hepatic clearance (CL) prediction used worldwide, remains controversial due to systematic underprediction. Among the various probable factors, the original assumption of the hepatic mathematical model (i.e.

Effect of repeated Shengmai-San administration on nifedipine pharmacokinetics and the risk/benefit under co-treatment.

Herbal interactions with nifedipine/felodipine through cytochrome P450 (CYP) 3A inhibition is significant in humans. Shengmai-San (SMS), a three-herbal formula of Chinese medicine, is commonly prescribed in Asia populations for cardiovascular disorders. This study aimed to elucidate the impact of SMS on nifedipine/felodipine treatment by the findings from rat pharmacokinetic study of nifedipine to the retrospective cohort study of patients with hypertension.

Precisely adjusting the hepatic clearance of highly extracted drugs using the modified well-stirred model.

Hepatic clearance has been widely studied for over 50 yr. Many models have been developed using either theoretical or empirical tests to predict drug metabolism. The well-stirred, parallel-tube, and dispersion metabolic models have been extensively discussed.

Effects of Shengmai San on key enzymes involved in hepatic and intestinal drug metabolism in rats.

Ethnopharmacological Relevance: Shengmai San (SMS) has been commonly used as a traditional Chinese medicine for the treatment of cardiovascular disorders, of which drug interactions need to be assessed for the safety concern. There is little evidence for the alterations of hepatic and intestinal drug-metabolizing enzymes after repeated SMS treatments to assess drug interactions.

Aim Of The Study: The studies aim to illustrate the effects of repeated treatments with SMS on cytochrome P450s (CYPs), reduced nicotinamide adenine dinucleotide (phosphate)-quinone oxidoreductase (NQO), uridine diphosphate-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) using in vivo rat model.

Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel-Tube Models over the Well-Stirred Model of Organ Elimination?

In reviewing previously published isolated perfused rat liver studies, we find no experimental data for high-clearance metabolized drugs that reasonably or unambiguously support preference for the dispersion and parallel-tube models versus the well-stirred model of organ elimination when only entering and exiting drug concentrations are available. It is likely that the investigators cited here may have been influenced by: 1) the unphysiologic aspects of the well-stirred model, which may have led them to undervalue the studies that directly test the various hepatic disposition models for high-clearance drugs (for which model differences are the greatest); 2) experimental assumptions made in the last century, which are no longer valid today, related to the predictability of in vivo outcomes from in vitro measures of drug elimination and the influence of albumin in hepatic drug uptake; and 3) a lack of critical review of previously reported experimental studies, resulting in inappropriate interpretation of the available experimental data. The number of papers investigating the theoretical aspects of the dispersion, parallel-tube, and well-stirred models of hepatic elimination greatly outnumber the papers that actually examine the experimental evidence available to substantiate these models.

A dual system platform for drug metabolism: Nalbuphine as a model compound.

Reaction phenotyping is a method commonly used for characterizing drug metabolism. It determines the drug metabolic pathways and ratios by measuring the metabolized fractions of individual enzymes. However, currently published results have focused on cytochrome P450s (CYPs), while not considering phase II metabolism.

Protein Binding and Hepatic Clearance: Re-Examining the Discrimination between Models of Hepatic Clearance with Diazepam in the Isolated Perfused Rat Liver Preparation.

This study re-examined the hepatic extraction for diazepam, the only drug for which isolated perfused rat liver (IPRL) studies have been reported not to be consistent with the well stirred model of organ elimination when only entering and exiting liver concentration measurements are available. First, the time dependency of diazepam equilibrium fraction unbound measurements from 4 to 24 hours was tested, reporting the continuing increases with time. The results showed that the time dependency of equilibrium protein-binding measurements for very highly bound drugs may be an issue that is not readily overcome.

A practical thrice weekly ertapenem in hemodialysis patients.

Change of ertapenem dosage from 500 mg daily to thrice weekly after each hemodialysis session can maintain the plasma concentration above 2 mg/L, and be practical in hemodialysis patients.

A novel finding of nalbuphine-6-glucuronide, an active opiate metabolite, possessing potent antinociceptive effects: Synthesis and biological evaluation.

Nalbuphine, a partial agonist/antagonist opioid analgesic, is structurally related to morphine. It is equipotent to morphine and has no serious side effects. In the past few decades, studies focusing on morphine metabolism have indicated that one of its sugar-conjugated metabolites, morphine-6-glucuronide, exerts a higher analgesic effect than its parent drug.

Shenmai-Yin decreased the clearance of nifedipine in rats: The involvement of time-dependent inhibition of nifedipine oxidation.

The traditional Chinese herbal formula Shenmai-Yin (SY) and nifedipine have both been used to treat patients with cardiovascular disorders. Nifedipine is primarily oxidized by cytochrome P450 (CYP) 3A. The oxidation and pharmacokinetics of nifedipine were studied in rats in vitro and in vivo to illustrate the interaction of SY with nifedipine.

Fundamentals of Pharmacokinetics to Assess the Correlation Between Plasma Drug Concentrations and Different Blood Sampling Methods.

Purpose: Various blood collection methods were developed and used in the pharmacokinetic evaluation of drugs. However, the influence of different blood sampling methods on plasma drug concentrations has not been clarified. In the present study, we aimed to determine whether the plasma concentration of a target drug changes based on the collection site and elucidate the mechanism responsible for this change.

Potentiation of the anticoagulation effect of warfarin by the herbal remedy Shu-Jing-Hwo-Shiee-Tang in rats: The dosing regimen and pharmacokinetic interaction.

The herbal remedy Shu-Jing-Hwo-Shiee-Tang (SJHST) has been used in traditional Chinese medical care for the treatment of osteoarthritis. This study aims to examine the influence of SJHST on the oxidation and anticoagulation effect of warfarin in male rats. In three SJHST preparations (S1-S3), hesperidin, gentiopicrin, and paeoniflorin were identified as chemical marker ingredients.

Commonly used excipients modulate UDP-glucuronosyltransferase 2b7 activity to improve nalbuphine oral bioavailability in humans.

Purpose: Nalbuphine (NAL) is a potent opioid analgesic, but can only be administered by injection. The major aim of this study was to develop an oral NAL formulation employing known excipients as UDP-glucuronosyltransferase 2B7 (UGT2B7) inhibitors to improve its oral bioavailability.

Methods: Twenty commonly used pharmaceutical excipients were screened in vitro by using liver microsomes to identify inhibitors of UGT2B7, the major NAL metabolic enzyme.

Dietary flavonoids modulate CYP2C to improve drug oral bioavailability and their qualitative/quantitative structure-activity relationship.

This study aims to improve the drug oral bioavailability by co-administration with flavonoid inhibitors of the CYP2C isozyme and to establish qualitative and quantitative (QSAR) structure-activity relationships (SAR) between flavonoids and CYP2C. A total of 40 naturally occurring flavonoids were screened in vitro for CYP2C inhibition. Enzyme activity was determined by measuring conversion of tolbutamide to 4-hydroxytolbutamide by rat liver microsomes.