Drug Metabolism

xenobiotic

foreign chemicals from the external environment

endobiotic

endogenous chemicals synthesized by the body

ADME

absorption, distribution, metabolism, excretion

Phase I drug metabolizing enzymes

class of drug metabolizing enzymes that reveal or add a functional group to the drug

Phase II drug metabolizing enzymes

class of drug metabolizing enzymes that add small polar molecules to the phase one metabolites

What types of functional groups do Phase I enzymes add?

-OH, -NH2, COOH, -SH, -O-

What types of functional groups do Phase II enzymes add?

glucuronic acid, sulfate, glutathione, acetyl group

What is the purpose of the addition of functional groups?

increase hydrophilicity

What type of -biotic can be directly metabolized by phase II enzymes or excreted?

xenobiotic

What enzymes are involved in P1 reactions?

Cytochrome P450, flavin-containing monooxygenases, esterases

What enzymes are involved in P2 reactions?

UDP-glucoronosyltransferases, sulfotransferases, glutathione S-transferases, N-acetyltransferases, methyltransferases, amino acid conjugation enzymes

First-pass effect (metabolism)

phenomenon where only a small fraction of administered drug reaches systemic circulation

Enzyme inhibition

enzymes that decrease drug metabolism, leading to increased levels of drug in the body leading to accumulation and potential toxicity

Enzyme induction

enzymes that activate transcription and induce the expression of genes encoding drug-metabolizing enzymes so drug metabolism increases

What type of receptors are typically involved in enzyme induction?

nuclear receptors

Is enzyme inhibitor binding reversible or irreversible?

can be either

How do genetic polymorphisms impact drug metabolism?

SNPs in drug metabolizing enzymes can reduce, modify, or stop enzyme activity

How can drug metabolism impact the distribution or excretion of the drug or increase toxicity?

drug metabolism can yield toxic metabolites during breakdown, which can affect how much drug is distributed and how much is excreted

Why is it important to consider species differences in drug metabolism where developing a drug?

toxic metabolite formation may occur in humans but not other species

not all species have the same enzymes or enzyme levels

even studying drug metabolism in one type of cell (e.g. hepatocytes) presents limitations

What mechanisms regulate the levels and activity of drug metabolizing enzymes?

enzyme inducers, enzyme inhibitors, inflammation

Describe UDP-glucuronosyltransferases and their function

type of P2 drug metabolizing enzyme

function → glucuronic acid conjugation

Describe sulfotransferases and their function

type of P2 drug metabolizing enzyme

function → sulfate group conjugation

Describe glutathione s-transferases and their function

type of P2 drug metabolizing enzyme

function → glutathione conjugation of electrophiles

Describe n-acetyltransferases and their function

type of P2 drug metabolizing enzyme

function: acetylation of arylamides and hydrazines

Describe methyltransferases and their function

type of P2 drug metabolizing enzyme

function: transfer methyl groups

Describe amino acid conjugation enzymes and their function

type of P2 drug metabolizing enzyme

function: conjugate xenobiotics with Gly, Glu, taurine

What are the major CYP450s?

CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP1A2

Describe CYP3A4 and its function

type of P1 drug metabolizing enzyme

function: involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids

Describe CYP3A5 and its function

type of P1 drug metabolizing enzyme

function: involved in the metabolism of steroid hormones and vitamins

Describe CYP2D6 and its function

type of P1 drug metabolizing enzyme

function: involved in the metabolism of fatty acids, steroids and retinoids

Describe CYP2C9 and its function

type of P1 drug metabolizing enzyme

function: involved in the metabolism of various endogenous substrates, including fatty acids and steroids

Describe CYP2C19 and its function

type of P1 drug metabolizing enzyme

function: involved in the metabolism of polyunsaturated fatty acids

Describe CYP2E1 and its function

type of P1 drug metabolizing enzyme

function: involved in the metabolism of fatty acids

Describe CYP1A2 and its function

type of P1 drug metabolizing enzyme

function: involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins

Where are CYPs typically located in the cell?

ER PM (primarily in liver)

Where does phase 2 metabolism typically occur?

cytoplasm or ER (for glucoronidation) of hepatocytes

Are phase 1 or phase 2 drug metabolism reactions quicker?

phase 2