Search results for " enzyme"
showing 10 items of 791 documents
An update on metabolism studies using human hepatocytes in primary culture
2008
Background: Cultured human hepatocytes are the closest in vitro model to human liver and constitute a very predictive model for drug metabolism in vivo. The variability observed in human hepatocytes reflects the existing phenotypic heterogeneity of cytochrome P450 expression in human liver. Objectives: As drug metabolism is the major source of pharmacokinetic variability in human beings, the main areas of current drug metabolism research in human hepatocytes are reviewed. Methods: To speed up the selection of drug candidates, the evaluation of metabolic stability, metabolite profiling and identification, and drug–drug interaction potential are key issues in drug development. Results/conclus…
ACE inhibitor potentiation of bradykinin-induced venoconstriction
1997
1. Angiotensin-converting enzyme (ACE) inhibitors exert their cardiovascular effects not only by preventing the formation of angiotensin II (AII), but also by promoting the accumulation of bradykinin in or at the vessel wall. In addition, certain ACE inhibitors have been shown to augment the vasodilator response to bradykinin, presumably by an interaction at the level of the B2 receptor. We have investigated whether this is a specific effect of the ACE inhibitor class of compounds in isolated endothelium-denuded segments of the rabbit jugular vein where bradykinin elicits a constrictor response which is exclusively mediated by activation of the B2 receptor. 2. Moexiprilat and ramiprilat (< …
Transcriptional regulation and expression of CYP3A4 in hepatocytes.
2007
CYP3A4 is the most abundantly expressed drug-metabolizing P450 enzyme in human liver and contributes to the metabolism of a large number of drugs in use today. CYP3A4 is constitutively expressed in adult hepatocytes but it can also be transcriptionally induced by a variety of structurally diverse xenochemicals. CYP3A4 strongly contributes to the important variability in the therapeutic and toxic effects of drugs owing to the major role it plays in xenobiotic metabolism and the large intra- and inter-individual variability to which it is subjected. The functional examination of up to 13 kb of the CYP3A4 5'-flanking region has revealed that the regulation of this gene is a complex issue, with…
Strategies and Molecular Probes to Investigate the Role of Cytochrome P450 in Drug Metabolism
2003
Drug metabolism is the major determinant of drug clearance and, because of polymorphic or inducible expression of drug-metabolising cytochrome P450s (CYPs), is the factor most frequently responsible for interindividual differences in pharmacokinetics. A number of well characterised CYP substrates and inhibitors have been identified that allow precise measurements of individual CYP isoforms. Their use, alone or in combination, facilitates the phenotype characterisation of hepatocytes in vitro and in vivo. Two procedures are used for in vitro investigation of the metabolic profile of a drug: incubation with microsomes and incubation with metabolically competent cells. The major limitation of …
Fluorescence-based assays for screening nine cytochrome P450 (P450) activities in intact cells expressing individual human P450 enzymes.
2004
In this study we describe a battery of fluorescence assays for rapid measurement in intact cells of the activity of nine cytochromes P450 (P450s) involved in drug metabolism. The assays are based on the direct incubation of monolayers of cells expressing individual P450 enzymes with a fluorogenic substrate followed by fluorimetric quantification of the product formed and released into incubation medium. For each individual P450 activity, different fluorescence probes were examined, and the one showing the best properties (highest metabolic rates, lowest background fluorescence) was selected: 3-cyano-7-ethoxycoumarin for CYP1A2 and CYP2C19, coumarin for CYP2A6, 7-ethoxy-4-trifluoromethylcoum…
Effect of nutritional imbalances on cytochrome P-450 isozymes in rat liver
1988
Male Sprague-Dawley rats were fed for six weeks either a control diet containing 22% casein (C) and 5% fat (F) or a low-protein diet (6% C, 5% F) or high-lipid diet (30% C, 30% F). A group of rats received a control diet containing 50 ppm of Phenoclor DP6. Three major forms of cytochrome P-450, UT 50, BP 3a and MC 2 were purified from livers of DP6-fed rats and only two forms, UT 50 and PB 3a, were purified from control and dietary groups. The amino acid composition and the catalytic activities towards all substrates tested were only significantly modified in the purified UT 50 P-450 isozyme from rats fed the low-protein diet. The N-terminal sequence analysis shows that cytochrome P-450 UT …
Long-term treatment with the ace inhibitor captopril, alone or in combination with hydrochlorothiazide, in elderly hypertensives: Effects on blood pr…
1993
Abstract The efficacy and tolerability of long-term treatment with the angiotensin converting enzyme inhibitor captopril was evaluated in elderly hypertensive subjects. One hundred thirty patients were studied (61 men and 69 women; mean age, 68.33 ± 5.49 years), all with mild to moderate arterial hypertension (mild = 90–105 mmHg; moderate = 105–115 mmHg). Patients with secondary hypertension were excluded from the study. After a 2-week drug washout, patients were given captopril 25 to 100 mg/day alone or in combination with hydrochlorothiazide (HCTZ) 25 mg/day for 15 weeks. After 2 weeks of treatment, significant decreases in systolic and diastolic blood pressures were observed (P
Prescription patterns of angiotensin-converting enzyme inhibitors for various indications: A UK population-based study
2018
AIM: Angiotensin‐converting enzyme inhibitors (ACEIs) are widely prescribed for several cardiovascular indications. This study investigated patterns of ACEI use for various indications. METHODS: A descriptive, retrospective population‐based study was conducted using data from the UK Clinical Practice Research Datalink. Patients starting ACEIs (2007–2014) were selected and ACEI indications were retrieved from electronically recorded medical records. Stratified by indication, we distinguished between persistent and nonpersistent ACEI use, considering a 6‐month interval between two prescription periods as a maximum for persistent use. Five‐year persistence rates for various indications were ca…
Soil enzyme assays using p-nitrophenyl derivatives: an inter-laboratory comparison
2011
Reproducibility and reliability of soil enzyme assays need to be validated by comparing results among different labs. The Italian Group of Enzymology organized a ring test among five labs. Beta-glucosidase, acid- and alkaline phosphatase activities were chosen as they are all measurable by using substrates with wide applicability, i.e. p-nitrophenyl derivatives. The five labs preliminarily agreed and standardised the specific methodological procedure for each enzymatic activity, also taking into account factors such as practicability and equipment availability. Nine soils with contrasting physico- chemical and biological properties were adequately sampled, pre-treated and sieved, in order t…
Current Evidence, Challenges, and Opportunities of Physiologically Based Pharmacokinetic Models of Atorvastatin for Decision Making
2021
Atorvastatin (ATS) is the gold-standard treatment worldwide for the management of hypercholesterolemia and prevention of cardiovascular diseases associated with dyslipidemia. Physiologically based pharmacokinetic (PBPK) models have been positioned as a valuable tool for the characterization of complex pharmacokinetic (PK) processes and its extrapolation in special sub-groups of the population, leading to regulatory recognition. Several PBPK models of ATS have been published in the recent years, addressing different aspects of the PK properties of ATS. Therefore, the aims of this review are (i) to summarize the physicochemical and pharmacokinetic characteristics involved in the time-course o…