Drug Metabolism & Transporters

Enzyme Inhibition

TREnzim İnhibisyonu
Also known as:Metabolic inhibition

A reduction in the activity of a drug-metabolizing enzyme by a co-administered drug or other substance, which lowers the clearance of drugs dependent on that enzyme and raises their concentrations.

Formula

AUCi / AUC = 1 / [fm / (1 + [I]/Ki) + (1 − fm)]

In depth

Inhibition may be reversible (competitive, non-competitive or uncompetitive) or irreversible (mechanism-based). Reversible inhibition acts as soon as inhibitor concentrations are sufficient and fades as the inhibitor is eliminated. In the basic static model, the rise in victim-drug exposure (AUCi/AUC) depends on the inhibitor concentration [I] relative to its inhibition constant Ki and on fm, the fraction of the victim's clearance handled by the inhibited enzyme; the victim reaches a new steady state after about four to five of its new, longer half-lives.

Regulatory guidance (e.g. FDA) classifies inhibitors as strong, moderate or weak when they increase the AUC of a sensitive index substrate ≥5-fold, ≥2- to <5-fold, or ≥1.25- to <2-fold, respectively.

Clinical pearl

Unlike induction, inhibition takes effect within days; adding fluconazole to warfarin or clarithromycin to tacrolimus calls for closer monitoring, dose adjustment or an alternative agent.

Example drugs

Ketoconazole Clarithromycin Fluconazole Fluoxetine Ritonavir
TRIn Turkish

Enzim İnhibisyonu

Birlikte kullanılan bir ilacın veya başka bir maddenin ilaç metabolize eden bir enzimin aktivitesini azaltması; böylece bu enzime bağımlı ilaçların klirensini düşürüp konsantrasyonlarını yükseltmesidir.

İnhibisyon geri dönüşümlü (yarışmalı, yarışmasız veya unkompetitif) ya da geri dönüşümsüz (mekanizma temelli) olabilir. Geri dönüşümlü inhibisyon, inhibitör konsantrasyonu yeterli düzeye ulaşır ulaşmaz başlar ve inhibitör elimine edildikçe azalır. Temel statik modelde etkilenen ilaca maruziyetteki artış (AUCi/AUC), inhibitör konsantrasyonunun [I] inhibisyon sabitine (Ki) oranına ve etkilenen ilacın klirensinin inhibe edilen enzimce gerçekleştirilen fraksiyonuna (fm) bağlıdır; etkilenen ilaç, uzamış yeni yarılanma ömrünün yaklaşık dört-beş katı sürede yeni kararlı duruma ulaşır.

Düzenleyici kılavuzlar (ör. FDA) inhibitörleri, duyarlı bir indeks substratın AUC değerini sırasıyla ≥5 kat, ≥2 ile <5 kat veya ≥1,25 ile <2 kat artırmalarına göre güçlü, orta veya zayıf olarak sınıflandırır.

İndüksiyonun aksine inhibisyon günler içinde etkisini gösterir; varfarine flukonazol ya da takrolimusa klaritromisin eklenmesi yakın izlem, doz ayarlaması veya alternatif bir ilaç gerektirir.

Diğer adları:Metabolik inhibisyon
Updated 24.09.2026 2 views Educational reference — verify against current sources before clinical use.

Read next

Mechanism-Based InhibitionMekanizma Temelli İnhibisyon

Irreversible or quasi-irreversible enzyme inactivation in which the enzyme converts the inhibitor into a reactive intermediate that binds covalently or tightly to it, so activity returns only as new enzyme is synthesized.

 Enzyme InductionEnzim İndüksiyonu

An increase in the amount and activity of a drug-metabolizing enzyme or transporter, usually through enhanced gene transcription, caused by repeated exposure to a drug or other xenobiotic.

 Inhibition Constantİnhibisyon Sabiti

The equilibrium dissociation constant of an inhibitor from its enzyme, receptor or transporter; an assay-independent measure of inhibitor affinity, with lower Ki values indicating more potent inhibition.

 Cytochrome P450Sitokrom P450

A superfamily of heme-containing monooxygenase enzymes, located mainly in the endoplasmic reticulum of hepatocytes and enterocytes, that catalyze most phase I oxidative drug metabolism.

 Perpetrator and Victim DrugsEtkileyen ve Etkilenen İlaçlar

Terms used in drug interaction analysis for the drug that causes an interaction (perpetrator or precipitant) and the drug whose concentrations or effects it alters (victim or object).

 Pharmacokinetic InteractionFarmakokinetik Etkileşim

An interaction in which one drug alters the absorption, distribution, metabolism or excretion of another, so that the concentrations of the affected drug change rather than its concentration–effect relationship.