PDA Final (Metabolism, Transport, & Interactions)

Drug metabolism

process where drug is chemically converted to a metabolite

an enzymatic process

allows drugs to cross lipid bilayers and be eliminated through urine or bile

Why does the body metabolize drugs?

To reach target receptors, drugs must be lipophilic to cross lipid bilayers.

4 outcomes of metabolism

inactivation (active drug → inactive form)

activation (prodrugs) (inactive drug → active drug)

maintained activity (active drug → active metabolite (longer t_1/2)

toxification (active drug → toxic metabolite) (ex: Tylenol overdose)

primary sites of metabolism

liver

small intestine

large intestine

metabolism in the small intestine

utilized in oral absorption using the portal vein to the liver

first pass metabolism

3 barriers to reach the bloodstream

gut lumen

gut wall [travel through portal vein]

liver [travel through hepatic vein]

Fraction of drug that reaches systemic circulation

bioavailability (F)

phase I metabolism

Goal?

Major Enzymes?

Reactions?

introduce/ expose functional groups - to make drug more polar

using CYP450 enzymes

oxidation (most common)

reduction

hydrolysis

Why can’t Nitroglycerin be taken orally?

Gets metabolized too fast, not enough left for bioavailability

Regulation CYP450 enzymes

found in mitochondrial and smooth ER to oxidize substances

Requirement: NAPDH reducing agent as a cofactor

induction - slows drug onset and increases clearance = more enzyme

inhibition - increases drug onset and dec/no change to clearance = less enzyme

phase II metabolism

improve water solubility through conjugation to ensure excretion

phase III metabolism

transport

Which phases of metabolism does Buprenorphine undergo? (SUD treatment via CYP3A4)

Phase 1 and 2

How does enzyme expression influence clearance and exposure?

Not expressing enzyme = decreased CL and increased AUC

Expressing too much enzyme = increased CL and decreased AUC

hPEPT1 and acyclovir

mechanism of prodrug formation where addition of amino acid group allows for transport from lumen to blood

acyclovir has poor oral absorption, but its prodrug (valacyclovir) uses hPEPT1 to increase permeability.

PXR

molecule sensor

when bound, the ligand-PXR complex is able to enter the nucleus and bind to the DNA promoter

induces transcriptional induction and increases CYP3A4

can have both inhibitory or excitatory action where no net effect can occur

drugs that utilize CYP2C9

warfarin

NSAIDS

Sulfonylureas

drugs that utilize CYP2C19

clopidogrel

black box warning for poor metabolizers

drugs that utilize CYP2D6

codeine - black box for children/breastfeeding

thioridazine (antipsychotic) - black box for poor metabolizers 2d6 cannot be induced

Rifampin and Tacrolimus Interaction

Rifampin decreases the bioavailability of tacrolimus. It does not inhibit the metabolism of tacrolimus; instead, it induces CYP enzymes, leading to decreased exposure (and plasma concentration) to tacrolimus. Management options include increasing the tacrolimus dose, selecting an alternative drug not affected by rifampin, or administering an additional medication that is not influenced by this interaction.

inhibition of CYP pathway leads to…

increases exposure and AUC

conjugation

covalent links with polar endogenous molecules to ensure secretion

requirement: transferase

rate limiting steps of metabolism

perfusion: how much blood reaches the liver

capacity: amount of enzyme activity

factors that affect metabolism

pharmacogenomics

age

disease state

extrinsic factors

transporters

location:

function:

contribution:

location: gut, liver, kidney, brain

function: move endogenously or exogenously

contribute to drug-drug interactions

types of movement across the membrane

carrier mediated

passive diffusion

vesicular trafficking

how are transporters classified

direction

outcome (absorb/secrete)

need for ATP

location

major human transporters

ATP binding cassette

solute carriers

transport in the small intestine

influx and efflux

PEPT1: alters permeability of the drug through addition of amino acids

transporters in the blood brain barrier

primarily efflux transporters that contribute to the difficulty for uptake

Passive, Facilitative, vs. Active transporters

Passive transporters - no energy; high to low; random

Facilitative transporters - passive; down concentration gradient; no energy

Active transporters - against concentration gradient; energy, saturable

Blockage of efflux transporter

more drugs into body

decreased plasma concertation

decreased bioavailability

OATP transporters

Uptake transporters bring drugs into the lumen. Once inside, the drug can diffuse to the smooth ER where CYP enzymes metabolize it.

MRP transporters

Efflux transporters that pump drug out of the cell. MRPs are essential for clearing metabolized drug after CYP + Phase II processing.

Grapefruit juice – effect on CYP3A4 and drug metabolism

Grapefruit juice inhibits intestinal CYP3A4

→ less first‑pass metabolism

→ more parent drug reaches systemic circulation

→ higher drug levels and lower metabolite formation

Systemic vs. Local Effect — What’s the difference?

Systemic effect: Change in plasma drug concentration (PK).

Local effect: Change in drug concentration inside the target tissue/cell (PD).

Transporter changes can affect one, the other, or both depending on location and direction of transport.

Liver Uptake Transporter ↓(e.g., ↓ OATP activity) — What happens?

Less drug enters hepatocytes → ↓ local hepatic effect (PD change)

More drug stays in systemic circulation → ↑ systemic exposure (PK change)

• Example: Statins rely on OATP to enter liver; reduced uptake → higher plasma statin levels but weaker cholesterol‑lowering effect.

Liver Efflux Transporter ↓ (e.g., ↓ MRP2) — What happens?

Efflux blocked → drug/metabolite trapped inside hepatocyte

Systemic PK usually unchanged (drug already inside liver; efflux doesn’t control plasma levels)

Local hepatic exposure ↑ → PD effect changes
Example: Higher intracellular statin concentration → potentially stronger liver‑specific action or toxicity.

Relationships between k, CL, Vd, t_1/2, AUC

k depends on CL and Vd

if CL and Vd have same magnitude of change = no change in k

if k changes then t_1/2 changes

k and t_1/2 = inverse relationship

CL and AUC have inverse relationship

Consequences of Drug Interactions on pharmacokinetics and pharmacodynamics?

Pharmicokinetics - effect of drug on another drug’s kinetics (ADME)

Pharmacodynamics - effect of drug on another drug’s pharmacological activity

Saint John's wort

CYP3A4 acceleration

Accelerated metabolism of many drugs (reduce efficacy) - SSRIs, warfarin, cancer and HIV drugs

reduces efficacy for Combined Oral Contraceptives (COC)

grapefruit juice

contains furanocoumarin which selectively inhibits CYP3A4

reduces efficacy in calcium channel blockers by preventing elimination

components of gene regulation

short specific stretches of DNA

gene regulatory proteins

tells gene when, where and how much to express

how is a gene controlled

upstream promotor

transcription factor

RNA polymerase

nuclear receptors

ligand activated regulatory proteins or transcription factors

components of nuclear receptors

DNA binding domain

ligand binding domain

activation function 2

coactivator

unbound: repression

bound: activation

Drugs that Induce Metabolizing Enzymes

PXR (Pregnane X Receptor) is a xenobiotic receptor that induces drug-metabolizing enzymes, enhancing the metabolism of certain drugs by increasing enzyme expression in metabolizing tissues.

Does PXR-induced enzyme expression always lead to functional changes in drug metabolism?

No; various factors, such as the specific substrate being metabolized or the presence of other interacting drugs, can influence the overall metabolic outcome, meaning that increased enzyme levels do not guarantee enhanced drug metabolism.

Anti-COVID drug paxlovid

protease inhibitor antiviral (Nirmatrelvir) + CYP3A4 inhibitor (Ritonavir)

by inhibiting CYP3A4, the antiviral is able to remain in circulation and the function is enhanced

Warning label for COC (estrogen and progestin are substrates of CYP3A4)

CYP substrate + CYP inhibitor =

CYP substrate + CYP inducer

CYP substrate + CYP inhibitor → INCREASED substrate concentration → toxicity

CYP substrate + CYP inducer → DECREASED substrate concentration → low efficacy