9/17 Drug metabolism and Transport

Solute Carriers (SLCs)

proteins in the cell membrane that transport substances such as nutrients, ions, and some drugs across the membrane

types of Solute Carriers (SLCs)

Passive transport, coupled transport, Exchange transport

Passive transport

no energy where substance goes along concentration gradient (high conc. to low conc.)

coupled transport

substance goes against concentration gradient where coupled to the movement of another substance (low conc. to high conc.)

Exchange transport

One substance goes into the cell while another comes out

SLCs naming

Gene names and then separated in subfamily

families are separated into roles and/or >20-25% amino acid sequence similarities

Gene names of SLCs

root symbol SLC, numeral and letter identifier of
families, then numerical representation of individual transporter

Facilitative glucose transporter (GLUT)

family: SLC2
Subfamily: A, B, C, D, E, F, G (SLC2A)
Glucose Transporter: SLC2A1 (GLUT1)

endogenous molecules

naturally occurring substances produced in body

how drugs can use SLC transporters to enter cells

drugs can be similar to endogenous molecules and be picked up by SLC

International Transporter Consortium (ITC)

identified SLC transporters that are especially important for drug movement in the body

different tissues have different SLC transporters

different tissues

express different amounts of each SLC transporter

SLC transporters are not equally present in every tissue

High SLC expression

that tissue has a lot of that transporter

Low SLC expression

that tissue has very little of that transporter

Substrates will have greater accumulation

in tissues with transporter expression

More expression of a transporter

more uptake of a drug that uses that transporter → more drug accumulates inside the cell

Oxaliplatin

anticancer drug containing platinum, it kills cancer cells largely by forming platinum-DNA adducts, which damage/interfere with DNA and prevent cells from functioning and dividing normally

Substrate

molecule that a transporter can recognize and transport

OATP1B1

important SLC transporter in the liver that takes drugs, especially statins from the blood into liver cells for their action and/or eventual metabolism and clearance

reduced function of OATP1B1

less drug enters the liver → more drug remains in the blood → increased systemic drug exposure → potentially increased toxicity

statins

substrates of OATP1B1, meaning OATP1B1 helps transport them from the blood into hepatocytes (liver cells)

Drug metabolism

helps the body eliminate lipophilic drugs by converting them into more polar, water-soluble compounds that can be excreted more easily

Xenobiotic

substance foreign to the body, such as a drug, toxin, or environmental chemical

Renal excretion

removal of a drug/metabolite by the kidneys into urine

Reabsorption

drug moves from the kidney tubule back into the blood instead of being excreted

Metabolism accounts for a large portion

of drug elimination, and CYP enzymes especially CYP3A4 are major contributors

28%

percentage of drug Cytochrome P450 has eliminated

25%

percentage of drug is eliminated through the kidneys → urine, without needing metabolism

6%

hepatobiliary

drug is eliminated through the liver → bile

10%

percentage of drug eliminated by glucuronidation (phase II)

liver (hepatocytes)

main site of drug metabolism, but metabolism can also occur in the intestine and many other tissues

phase I and phase II metabolism

Intestinal wall

can also metabolize drugs by enterocytes

oral drug pathway

intestine → portal blood → liver → systemic circulation

First-pass effect/metabolism

metabolism of an orally administered drug in the intestinal wall and/or liver before it reaches systemic circulation

Microsomes

small membrane vesicles formed from fragments of the ER when cells are broken apart in the laboratory

lipophilic drugs

undergo phase I and/or phase II reactions to become more water soluble so drug can be excreted

Phase I metabolism

chemically modifies the drug to introduce or expose a functional group

-expose alcohol group

Phase I metabolism reactions

oxidation, reduction, and hydrolysis

CYP450 enzymes (oxidation)

Phase II metabolism

attaches a highly polar group to the drug or its Phase I metabolite, conjugation

oxidation

Loss of electron through addition of oxygen or removal of hydrogen

Reduction

Gain of electron through loss of oxygen or gain of hydrogen

Hydrolysis

enzymatic cleavage of a chemical bond by addition of water

CYP450 enzymes

use oxygen (O₂) and electrons ultimately supplied by NADPH to oxidize drugs, usually making them more polar

Monooxygenase

an enzyme system that uses O₂ and incorporates one oxygen atom into the substrate while the other oxygen atom is reduced to form water

CYP3A4

responsible for metabolism of ~50% of prescribed drugs

transferases

enzyme that transfers a chemical group from one molecule to another
Phase II enzymes

UGT (UDP-glucuronosyltransferase)

major Phase II enzymes that do glucuronidation

Glucuronidation

attaching glucuronic acid to a drug or metabolite

phase II rxn, UGT2B7 most common UGT enzymes

Sulfotransferase (SULT)

phase II rxn that adds a sulfate group (sulfation) from PAPS, the body’s sulfate donor

Glutathione-S-Transferase (GST)

enzyme that attaches glutathione to certain drugs or reactive metabolites

phase II

Amino acid conjugation

glycine and glutamate are added to drug by enzymes like glycine-N-acyltransferase

phase II

Acetylation

adding an acetyl group to a drug by enzymes NAT1 and NAT2 (N-acetyltransferase)

phase II

Methylation

phase II rxn adding a methyl group by enzymes methyltransferases, uses methyl group from SAM

Catechol-O-methyltransferase (COMT)

Thiopurine methyltransferase (TPMT)

Clearance

body's ability to remove/eliminate drug from the circulation

Parent drug

original drug before it is metabolized

Metabolism does not always

inactivate a drug

active parent drug can be metabolized into an active metabolite with similar activity, so drug effect may continue even while the parent drug is being cleared

bioactivation

when metabolism creates a more reactive/toxic product

two possible outcomes of metabolism

inactivate drug or make drug more harmful

Many adverse events

due to reactive metabolite formation (toxic)

Major regulatory drug development concern

prodrug

drug that is administered in an inactive or less-active form and is converted by metabolism into a more active form

codeine needs to be converted to morphine in body

Bioactivation

metabolism that converts a compound into a more pharmacologically active form

Enzyme inhibition

decreasing or stopping the activity of a drug-metabolizing enzyme, causing less metabolism by that enzyme

Mechanism-based inhibition

enzyme metabolizes an inhibitor into a reactive product that then covalently binds to and inactivates the enzyme

aka suicide inhibition bc inactivates itself

inhibition of a enzyme that normally metabolized and clears active drug

will decrease drug metabolism and clearance, causing the drug concentration to increase and potentially increasing the risk of toxicity

inhibition of enzyme that was activating a prodrug

will decrease prodrug metabolism, causing less active drug/metabolite to be formed and therefore decreasing the drug's effect

Enzyme induction

increasing the amount/activity of a drug-metabolizing enzyme, causing drugs handled by that enzyme to be metabolized faster

Drug doses are chosen

based on expected clearance and metabolism bc too little metabolism of active drug could cause toxicity risk but too much metabolism makes drug conc. too little

ABC transporters (ATP Binding Cassette Transporters)

use energy from ATP to pump drugs or metabolites out of cells (efflux), which can help with drug elimination

examples of ABC transporters

P-glycoprotein (Pgp/ABCB1)*
Breast Cancer Resistance Protein (BCRP/ABCG2)*
Bile Salt Export Pump (BSEP/ABCB11)
Multidrug Resistance Protein 2 (MRP2/ABCC2)

P-gp and BCRP

are ABC efflux transporters that pump drugs OUT of cells, especially in the intestine and blood-brain barrier, protecting the body by limiting drug/toxin entry

P-gp and BCRP are both expressed in

intestine and at the blood-brain barrier (BBB)

efflux transporters with a wide range of drug substrates

P-gp and BCRP

recognize drugs at/in cell membrane and pumps them out

codeine to morphine

phase I rxn where it removes a methyl group and reveals an OH group

Less P-gp activity

less drug pumped out → more drug accumulates in tissues

More P-gp activity

more drug pumped out → less drug exposure/absorption

what controls drug disposition and clearance

Transporters move drugs into or out of cells, while metabolic enzymes chemically change the drugs

Metabolic enzymes and transporters control

ADME, drug exposure, and therefore determine how much drug is in the body, how long it stays there, whether it works, and whether it becomes toxic

Therapeutic window

range of drug concentrations that is high enough to work but low enough to avoid unacceptable toxicity