Phase I Reactions

Phase I reactions are the first stage of drug metabolism, in which enzymes introduce or unmask a reactive functional group on a drug molecule through oxidation, reduction, or hydrolysis. These reactions, dominated by the cytochrome P450 enzymes, prepare lipophilic drugs for elimination and can produce either inactive metabolites, active metabolites, or occasionally reactive species.

Definition

Phase I reactions are functionalization reactions of drug metabolism in which oxidation, reduction, or hydrolysis introduces or exposes a polar functional group (such as a hydroxyl, amino, or carboxyl group) on a drug, typically as a preliminary step toward conjugation and excretion.

Scope

This topic covers the chemistry and enzymology of phase I (functionalization) metabolism - oxidation, reduction, and hydrolysis - the enzyme families that carry it out, and its consequences including bioactivation and the formation of reactive metabolites. It is a reference description of mechanisms and does not provide clinical or dosing guidance.

Core questions

• What chemical transformations define phase I metabolism, and which enzymes perform them?
• How can phase I reactions convert a drug into an active or a reactive metabolite?
• How does genetic variation in phase I enzymes alter drug clearance?

Key concepts

• Functionalization (oxidation, reduction, hydrolysis)
• Cytochrome P450-mediated oxidation
• Non-CYP phase I enzymes (flavin monooxygenases, esterases, epoxide hydrolases)
• Active and inactive metabolites
• Bioactivation and reactive metabolites
• Prodrug activation

Mechanisms

In phase I metabolism, enzymes add or expose a polar functional group on the drug. Oxidation, carried out mainly by the cytochrome P450 enzymes, is the most common route and includes hydroxylation, dealkylation, and related reactions; reduction and hydrolysis (the latter by esterases and amidases) handle other substrates (Wilkinson, 2005). The resulting metabolite may be pharmacologically inactive, may retain or gain activity (as when a prodrug is activated), or, in some cases, may be a chemically reactive species capable of binding cellular macromolecules - the process of bioactivation that can contribute to drug-induced toxicity (Park et al., 2005). Because the phase I enzymes, especially the CYPs, are genetically variable, the rate and balance of these transformations differ between individuals (Ingelman-Sundberg, 2004).

Clinical relevance

Phase I metabolism determines whether a drug is inactivated, activated, or converted to a potentially harmful metabolite, which helps explain differences in efficacy and in some adverse reactions. This entry describes those mechanisms for reference and is not a basis for individual dosing or treatment decisions.

History

The division of drug metabolism into a functionalization step and a subsequent conjugation step - later termed phase I and phase II - was articulated by R. T. Williams in the mid-twentieth century and remains the organising framework for the field. The later identification of the cytochrome P450 enzymes as the principal phase I oxidases, and recognition of bioactivation as a toxicological mechanism, refined this picture (Wilkinson, 2005; Park et al., 2005).

Key figures

• Grant Wilkinson
• Magnus Ingelman-Sundberg
• B. Kevin Park
• Munir Pirmohamed

Seminal works

• wilkinson-2005
• park-2005

Frequently asked questions

What is the difference between phase I and phase II metabolism?

Phase I reactions add or expose a functional group through oxidation, reduction, or hydrolysis, while phase II reactions attach a larger endogenous molecule (conjugation) to make the compound more water-soluble; phase I often precedes phase II but the two can also occur independently.

Can a phase I reaction make a drug more dangerous?

Sometimes - phase I metabolism can convert a drug into a chemically reactive metabolite (bioactivation), which in certain cases contributes to tissue toxicity such as drug-induced liver injury.