Drug Metabolism (Biotransformation)

Phase I reactions are catalyzed by: reactions

-C and O oxidation, dealkylation, others -N,S, and P oxidation -Hydrolysis of epoxides -reduction of alcohols -reduction of aldehydes -reduction of quinones

Phase I reactions are catalyzed by: enzymes (oxygenases)

-CYP 450 -FMO -mEH, sEH

Sites of biotransformation reactions: At the tissue level: every tissue has some metabolic activity

-Liver: main site -GI tract -Kidneys -Lungs

Phase II reactions are catalyzed by: Phase 2 tansferases

-Sulfotransferase (SULT) -UDP-glucuronsyltransferases (UGT) -Gluthiaone-S-transferases (GST) -N-Acetyltransferases (NAT) -Methyltransferases (MT)

Flavin-containing monooxygenases (FMOs)

-a family of enzymes (monooxygenases) -Localized in the ER of liver cells -Responsible for metabolic reactions involving nucleophilic nitrogen, sulphur, and phosphorous

Phase I reactions are catalyzed by: other enzymes

-alcohol dehydrogenase -aldehyde dehydrogenase -NADPH-quinone oxioreductase (NQO)

Phase II reactions: form a covalent link between phase I and metabolite and an *endogenously driven compound*

-conjugation

Major factors influencing drug metabolism

-genetics (ethnicity) -enzyme induction -enzyme inhibition

Drug metabolites are *generally*

-more *hydrophilic*, more water soluble, and thus more readily excreted -Pharmacologically inactive

Phase I reactions: introduces or unmasks a polar functional group

-oxidation -hydrolysis -reduction

Sites of biotransformation reactions: At the cell level

-smooth ER -cytosol -mitochondria

Metabolism of phenytoin by phase I cytochrome P450 (CYP) and phase II (UGT)

CYP facilitates 4-hydroxylation of phenytoin. The hydroxyl group serves as a substrate for UGT that conjugates a molecule of glucuronic acid using UDP-glucuronic acid (UDP-GA) as a cofactor. This converts a very *hydrophobic* molecule to a larger hydrophilic derivative that is elminated via the *bile*

Atorvastatin

CYP3A4

First Pass Phenomenon

Drugs are first absorbed through the *small intestine* and then arrive at the *liver* via the *portal circulation*

Significance: The lipophilic characteristics of the drugs promote their passage through biological membranes and access to the site of action.

However, those same characteristics hinder the drug's excretion from the body.

Phase I Reactions

I. Oxidative reactions -N-dealkylation -O-Dealkylation -Aliphatic hydroxylation -Aromatic hydroxylation -N-Oxidation -S-Oxidation -Deamination II. Hydrolysis reactions

Enzyme induction/inhibition (drugs, food, smoking)

Many drugs may increase or decrease the activity of various CYP isozymes either by inducing the biosynthesis of an *isozyme* (enzyme induction) or by directly inhibiting the *activity of the CYP* (enzyme inhibition). *This is a major source of adverse drug interactions*

"Activated oxygen" P450-substrate complex:

The potent oxidizing properties of activated oxygen allow oxidation of a large number of substrates -Substrate specificity is low (structurally diverse drugs and chemicals)

Aliphatic hydroxylation RCH2CH3 RCHOHCH3

Tolbutamide, ibuprofen, phenobarbital, meprobamate, cyclosporine, midazolam

Metabolite

a more water soluble compound that can be easily excreted. The major organ for this process is the *liver*

Cytochrome P450 enzymes (CYPs)

a superfamily of enzymes (monooxygenases) -responsible for metabolizing the vast majority of drugs -enzyme structure contains heme

There will be *less active drug available for action in the body cells*

after this *first pass* through the Liver

Orally absorbed drugs

are carried through the portal vein into the liver *before* it reaches the rest of the body

CYPs nomeclature

at least 18 families of CYPs and 43 subfamilies

Alternative routes of administration (IV, IM, transdermal, sublingual)

avoid the first pass effect and are distributed around the body before reaching the liver

Hydrolysis reactions

carbamazepine, procaine, aspirin, clofibrate, meperidine, enalopril, cocaine, lidocaine, procainamide, indomethaci

N-Oxidation

chloropheniramine, dapsone, meperidine

S-Oxidation

cimetidine, chloropromazine, thioridazine, omeprazole

O-Deallkylation ROCH3 ROH + CH2O

codeine, indomethacin, dextromethorphan

In Phase II

conjugated drug is usually inactive

Deamination

diazepam, amphetamine

Drugs undergo considerable biotransformation before

entering the *systemic circulation*

Furanocoumarins

found in grapefruit have been found to inhibit CYP3A4-mediated metabolism of certain medications

Pharmacogenetics

hereditary influences on drug responses, refers to variations in which individuals metabolize drugs

N-Dealklylation RNHCH3 RNH2 + CH2O

imipramine, diazepam, codeine, erythromycin, morpine, tamoxifen, theophylline, caffeine

Polycyclic aromatic hydrocarbons

in tobacco smoke are believed to be responsible for the induction of a variety of CYP450 enzymes

Drugs undergoing *glomerular filtration*

may get reabsorbed back into the systemic circulation via the *distal convoluted tubules*

Aromatic hydroxylation

phenytoin, phenobarbital, propanolol, ethinyl estradiol, amphetamine, warfarin

Biotransformation

process by which the body changes the chemical structure of a drug to another form called a *metabolite*

First-Pass effect

refers to the fraction of lost drug during the process of absorption: -metabolism in the gut wall -metabolism in the liver -excretion into bile

Following phase I

the drug may be activated, unchanged, or, most often, inactivated

Circadian Rhythms

the rate of drugs absorption, hepatic clearance, half-life and duration of action, have all been shown to differ depending upon the time of day a drug is administered

Most drugs must first be *metabolized* using

two general sets of reactions, called phase I and phase II