9/17 ch. 4 required reading: drug biotransformation

most drugs are made to be lipophilic

so they can cross the membranes

downside of being lipophilic

stays in body for a long time but we want to drug to do its job and then be excreted

solution to get rid of lipophilic drugs in body

body (and enzymes) has the ability to metabolize or biotransform the lipophilic structure to hydrophilic structure

2 categories of enzymes that biotransform

phase I

phase II

purpose of metabolism/biotransformation

decrease lipid solubility and increase ionization (make it more water soluble) to increase body excretion

phase 1

different enzymes that add or expose oxygen to make it more water soluble

phase I reaction

oxidation hydrolysis

cytochrome P450

enzyme family that biotransforms by oxidation hydrolysis, it adds a oxygen to a bond causing it to be more water soluble

-phase i

esterase hydrolysis

enzyme that biotransforms exposing an oxygen by breaking ester bonds to make two molecules with OH groups, makes it more water soluble

--phase i

amidase hydrolysis

enzyme that biotransforms by breaking amide bonds and breaks the bond to expose the oxygen to form OH → more water soluble

phase i

phase II

conjugation where different groups of enzymes add conjugates/groups/structures that are more water soluble

phase II reactions

glucuronidation, sulfation, methylation, acetylation, amino acid addition, and glutathione

glucuronidation enzyme (glucuronal transferase)

transfers glucuronide molecule on the drug to make it more water soluble

phase II

drugs can go thru

either phase I or phase II or both in any order

requirement for phase II

drug must have some functional group to act on (-OH, -SH, NH, -COOH)

drugs can become toxic

some enzymes from phase I or phase II reactions can make a drug toxic

drugs can be biotransformed into

active drugs, and/or into toxic metabolites

benzene

doesn’t have a functional group to be able to undergo phase II reactions

xenobiotics

substances absorbed across the lungs or skin

chemical substance found within an organism that is not naturally produced or expected to be there

mammalian drug biotransformation systems evolved from

the need to detoxify and eliminate plant and bacterial bioproducts and toxins, which later extended to drugs and other environmental xenobiotics

Renal excretion

plays a pivotal role in terminating the biologic activity of some drugs

lipophilic xenobiotics

are transformed to more polar and hence more readily excreted products

some biotransformation products

have enhanced activity or toxic properties

Phase I reactions usually convert

the parent drug to a more polar metabolite by introducing or unmasking a functional group

phase I metabolites

if sufficiently polar, they can be readily excreted but many products are not eliminated rapidly and undergo a reaction with a endogenous substrate like sulfuric acid to form a highly soluble polar conjugate (phase II)

sometimes phase I product

isn’t water soluble enough to be eliminated efficiently so it goes onto phase II where it adds a very polar group (conjugation)

-phase I does not always have to go first

After oral administration

many drugs are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism

-first-pass effect

First-pass effect

metabolism of an orally administered drug before it reaches systemic circulation, primarily involving the intestinal wall and liver

Bioavailability (F)

the fraction of the administered drug that reaches systemic circulation unchanged

Extensive first-pass metabolism

much of an oral drug is metabolized in the intestine/liver before reaching systemic circulation, resulting in low oral bioavailability

so another route is needed so the drug work its effect

Gut microorganisms

contain enzymes that can metabolize (biotransform) drugs and their metabolites in the lower GI tract

Gastric acid in stomach

Some drugs are chemically unstable in acid, so stomach acid can break them down

ex penicillin

Digestive enzymes in GI tract

designed to break down nutrients such as proteins, so if the drug is a peptide/protein, those enzymes may recognize it as something to digest

ex insulin

Enzymes in the intestinal wall

intestinal cells contain drug-metabolizing enzymes

two ways a drug can be chemically changed

Spontaneously - no enzyme needed

Enzyme-catalyzed - more common

microsomes

the small pieced endoplasmic reticulum (ER) are broken into

rough microsomes

protein synthesis

smooth microsomes

rich in enzymes responsible for oxidative drug metabolism aka mixed function oxidases (MFOs), or monooxygenases which require a reducing agent NADPH

how CYP450 actually performs Phase I oxidation

requires NADPH + O₂. NADPH transfers electrons through CPR (using FAD and FMN) to CYP450. CYP450 uses those electrons and O₂ to oxidize the drug: one oxygen enters the drug and the other forms H₂O

Microsomal drug oxidations require

P450, P450 reductase, NADPH, and molecular oxygen

CYP3A4 alone

responsible for the metabolism of over 50% of the prescription drugs metabolized by the liver

P450 enzymes (CYP)

large family of enzymes that metabolize drugs and other chemicals, especially in the liver

P450 enzymes can be induced

by substrate stabilization which is decreased degradation

suicide inhibitors

drugs/chemicals that an enzyme starts to metabolize, but during that process the chemical turns into something that permanently inactivates the enzyme itself

Phase II reactions are relatively faster than

P450-catalyzed reactions