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Plant-Based Adjunct Therapy for Tuberculosis
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Lydia Gibango, Anna-Mari Reid, Jonathan L. Seaman, Namrita Lall
Inhibition of cytochrome P450 enzymes results in a decreased rate of metabolism and excretion of drugs metabolized by these enzymes. This may concurrently result in the accumulation of the drug in the body, and toxicity may occur within 2–3 days, depending on the level of inhibition and the drug used. The clinical significance of enzyme inhibition interactions is dependent on the extent to which serum levels rise (Harris and Swart, 2005). Inhibitors inactivate specific CYP enzymes irreversibly. Metabolism will resume back to normality once the inhibitor has been cleared and new enzymes have been produced (Scripture et al., 2006).
Pharmacology of the Lower Urinary Tract
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Pedro Abreu-Mendes, João Silva, Francisco Cruz
The majority of anti-muscarinic drugs are metabolised by the P450 enzyme system.Carries risk of drug interactions causing enzyme inhibition/induction.
The Renin-Angiotensin System
Published in Austin E. Doyle, Frederick A. O. Mendelsohn, Trefor O. Morgan, Pharmacological and Therapeutic Aspects of Hypertension, 2020
The most widely used agents are the nonapeptide converting-enzyme inhibitor, SQ 20881, and angiotensin-II-receptor blocker, [Sar1,Ala8]-angiotensin II (also known as saralasin or PI 13), or other angiotensin analogues with aliphatic residues at position 8 of the molecule. Neither of these two named agents are ideal for the evaluation of the role of angiotensin II in the maintenance of blood pressure. Converting enzyme inhibition may impair the degradation of the hypotensive peptide, bradykinin, as well as block the formation of angiotensin II as discussed under Section II.C.2.C. Either of these actions could lower blood pressure. The [Sar1,Ala8]-angiotensin-II analogue, hereafter called “Saralasin” for brevity, has some agonist action on vascular smooth muscle and adrenal zona glomerulosa cells, and its use as a blocking agent may, therefore, underestimate the effect of angiotensin II in maintenance of blood pressure.490,654
Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Resorting to authoritative sources certainly reduces the risk of misapprehension, but for those who do not have a strong background in enzymology, attaining a proper understanding of mixed inhibition and its molecular determinants remains arduous. For example, Cornish-Bowden in “Fundamental of Enzyme Kinetics” clearly explains the limits of the formal two-site mechanism and suggests that mixed inhibition occurs mainly as a case of product inhibition with iso-mechanism enzymes12. Johnson, in “Kinetic Analysis for the New Enzymology”, adds that mixed inhibition, analogous to uncompetitive inhibition, occurs mainly with multi-substrate reactions, either as a form of product inhibition or, for ternary-complex mechanisms, when a dead-end inhibitor binds before the variable substrate.7 Copeland instead, in “Evaluation of Enzyme Inhibition in Drug Discovery”, mentions five mechanisms through which active site-directed inhibitors can cause inhibition patterns typical of mixed inhibition.3 However, these five mechanisms are treated as exceptions to a general rule. With the general rule being, again, the formal two-site mechanism.
Estimation of contribution of CYP2D6 to tipepidine metabolism in humans and prolongation of the half-life of tipepidine by combination use with a CYP2D6 inhibitor in chimeric mice with humanised liver
Published in Xenobiotica, 2023
Shun Hayashi, Hiroko Kawaguchi, Takao Watanabe, Izuru Miyawaki, Tatsuki Fukami, Miki Nakajima
One approach to prolong the half-life is increasing metabolic stability using enzyme inhibitors. There are examples of combinations of therapeutic drug and enzyme inhibitor, such as PREZCOBIX®, which is a combination of the HIV-treatment drug darunavir and the cytochrome P450 (P450, CYP) 3A4 inhibitor cobicistat (Kakuda et al. 2015), TS-1, which is a combination of the anticancer drug 5-FU and the dihydropyrimidine dehydrogenase inhibitor gimeracil (Inoue et al. 2007), and NUEDEXTA®, which is a combination of the emotion dysregulation drug dextromethorphan and the CYP2D6 inhibitor quinidine (Taylor et al. 2016). This approach is only effective when a therapeutic drug is selectively metabolised by a single drug-metabolizing enzyme and hepatic elimination is the major clearance pathway.
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
To gain further insight into the mechanism of hAChE inhibition, an enzyme kinetic study was performed on the most potent AChE inhibitor of the series (23). The graphical presentation of the steady-state inhibition data of compound 23 for hAChE is demonstrated in Figure 1. The analysis of the direct plots revealed a reduction of Vmax, whereas Km remained unchanged. These findings are consistent with a non-competitive mode of enzyme inhibition. In case of AChE, it means that the preferential binding site of propargyltacrines is the peripheral anionic site (PAS). From the perspective of AD therapy, this is a highly desirable effect since aggregation of amyloid-beta protein (Aβ) and subsequent neurotoxic cascade are catalysed particularly by the PAS of AChE39. Replots of the slope versus concentration of 23 gave an estimate of the competitive inhibition constant (Ki) of 12.39 ± 1.40 nM, which is consistent with the IC50 (hAChE) value obtained above.