Drug Metabolism & Transporters

Mechanism-Based Inhibition

TRMekanizma Temelli İnhibisyon
Also known as:Time-dependent inhibition · Suicide inhibition · MBI

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.

Formula

kobs = kinact × [I] / (KI + [I])

In depth

Mechanism-based (time-dependent) inhibition is recognized in vitro by inhibition that increases with preincubation time and requires NADPH. The observed inactivation rate constant (kobs) at inhibitor concentration [I] is described by kinact, the maximal inactivation rate constant, and KI, the inhibitor concentration giving half the maximal rate. Mechanisms include covalent binding to the apoprotein, alkylation of the heme, and formation of a metabolite–intermediate complex, as with macrolides and CYP3A4.

Because recovery depends on enzyme resynthesis rather than inhibitor elimination, the effect persists for days after the perpetrator is stopped and can build up with repeated dosing. Important examples include clarithromycin, erythromycin, diltiazem, ritonavir and grapefruit furanocoumarins (CYP3A4), and paroxetine (CYP2D6).

Clinical pearl

Stopping a mechanism-based inhibitor does not end the interaction at once: CYP3A4 activity may take days to recover after clarithromycin, so a washout should be considered before a sensitive substrate is restarted at full dose.

Example drugs

Clarithromycin Erythromycin Diltiazem Ritonavir Paroxetine
TRIn Turkish

Mekanizma Temelli İnhibisyon

Enzimin inhibitörü reaktif bir ara ürüne dönüştürdüğü ve bu ürünün enzime kovalent ya da çok sıkı biçimde bağlandığı, geri dönüşümsüz veya yarı geri dönüşümsüz bir inaktivasyondur; aktivite ancak yeni enzim sentezlendikçe geri kazanılır.

Mekanizma temelli (zamana bağımlı) inhibisyon in vitro olarak ön inkübasyon süresiyle artan ve NADPH gerektiren inhibisyonla tanınır. İnhibitör konsantrasyonu [I] iken gözlenen inaktivasyon hız sabiti (kobs), maksimal inaktivasyon hız sabiti kinact ve maksimal hızın yarısını sağlayan inhibitör konsantrasyonu KI ile tanımlanır. Mekanizmalar arasında apoproteine kovalent bağlanma, hem grubunun alkilasyonu ve makrolidler ile CYP3A4 örneğindeki gibi metabolit–ara ürün kompleksi oluşumu yer alır.

İyileşme inhibitörün eliminasyonuna değil enzimin yeniden sentezine bağlı olduğundan, etki etkileyen ilaç kesildikten sonra günlerce sürer ve tekrarlanan dozlarla birikebilir. Önemli örnekler klaritromisin, eritromisin, diltiazem, ritonavir ve greyfurt furanokumarinleri (CYP3A4) ile paroksetindir (CYP2D6).

Mekanizma temelli bir inhibitörün kesilmesi etkileşimi hemen sonlandırmaz: klaritromisin sonrasında CYP3A4 aktivitesinin toparlanması günler sürebilir; bu nedenle duyarlı bir substrata tam dozla yeniden başlamadan önce arınma süresi düşünülmelidir.

Diğer adları:Zamana bağımlı inhibisyon · İntihar inhibisyonu · Mekanizmaya dayalı inhibisyon
Updated 24.09.2026 0 views Educational reference — verify against current sources before clinical use.

Read next

Enzyme InhibitionEnzim İnhibisyonu

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.

 CYP3A4CYP3A4

The most abundant cytochrome P450 isoform in the human liver and small-intestinal epithelium, responsible for the oxidative metabolism of a large proportion of clinically used drugs.

 Grapefruit Juice InteractionGreyfurt Suyu Etkileşimi

An interaction in which furanocoumarins in grapefruit juice irreversibly inhibit intestinal CYP3A4, increasing the oral bioavailability of drugs that undergo extensive first-pass metabolism by this enzyme.

 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).

 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.

 Non-Competitive AntagonismYarışmasız Antagonizma

Antagonism that cannot be overcome by increasing the agonist concentration, because the antagonist binds irreversibly or acts at a site or step distinct from agonist binding; the maximal agonist response is reduced.