Clinical Pharmacogenomics: ADME, Psychotropics, Cardiology, and Oncology

Comprehensive vocabulary flashcards covering the pharmacogenomics of drug absorption, distribution, metabolism, excretion (ADME), psychotropics, cardiology medications, and oncology regimens.

Pharmacokinetics (PK)

The study of what the body does to a drug, encompassing drug bioavailability and the processes of absorption, distribution, metabolism, and excretion (ADME).

Pharmacodynamics (PD)

The study of what a drug does to the body, encompassing drug actions at intended targets (on-target efficacy) and unintended targets (off-target adverse drug reactions).

Major Facilitator Superfamily (MFS)

A large superfamily of membrane transport proteins that includes the Solute Carrier (SLC) family, comprising organic anion transporters (OATs), organic cation transporters (OCTs), and transporters for nucleotides, vitamins, and small peptides.

Solute Carrier (SLC) Family

Transporter proteins, such as OATs and OCTs, that mediate the uptake and influx of drugs and endogenous biomolecules across cellular membranes from the gut into blood and organ tissues.

ATP-Binding Cassette (ABC) Transporter Cycle

An energy-dependent transport mechanism in which substrate binding and ATP hydrolysis across two nucleotide-binding domains drive conformational changes that mediate substrate efflux out of the cell.

P-glycoprotein (P-gp)

An ATP-dependent efflux pump encoded by the $ABCB1$ (or $MDR1$) gene that actively exports xenobiotics out of cells across tissues such as the intestinal epithelium, liver canalicular membrane, and blood-brain barrier.

OATP1B1

An organic anion transporting polypeptide encoded by the $SLCO1B1$ gene that facilitates the hepatic uptake of endogenous molecules and drugs, including pravastatin and repaglinide.

Phase I Metabolism

Nonsynthetic enzymatic reactions—including oxidation, reduction, hydrolysis, and cyclization—that introduce or unmask polar functional groups to alter drug polarity and facilitate excretion or prodrug activation.

Cytochrome P450 Catalytic Cycle

A multi-step monooxygenase catalytic cycle where substrate binding to ferric $Cytochrome\text{ }P450^{+3}$ is followed by electron transfer from NADPH via NADPH-cytochrome P450 reductase, dioxygen binding, and oxygen insertion into the substrate, releasing the oxidized drug product and water.

Roche AmpliChip CYP450

A targeted commercial microarray designed to detect specific allelic variants of $CYP2D6$ and $CYP2C19$, the two genes responsible for the majority of inter-individual variability in drug metabolism.

Phase II Metabolism

Synthetic enzymatic conjugation reactions that attach polar, ionizable endogenous groups (such as acetyl, methyl, or glucuronidyl residues) to drugs or Phase I metabolites, yielding water-soluble, typically inactive products.

N-Acetyltransferases (NATs)

Phase II enzymes ($NAT1$ and $NAT2$) that transfer an acetyl group from acetyl-CoA onto terminal nitrogen residues of arylamines and hydrazines, responsible for the classic slow versus fast acetylator phenotypes.

Isoniazid Pharmacogenetics

The earliest reported human pharmacogenetic trait (1953), wherein slow $NAT2$ acetylators exhibit impaired drug detoxification leading to elevated hepatotoxicity risk, whereas rapid acetylators risk therapeutic failure.

Thiopurine S-Methyltransferase (TPMT)

A cytosolic Phase II conjugating enzyme that inactivates thiopurine medications, such as $6\text{-mercaptopurine}$ ($6\text{-MP}$) and azathioprine, by transferring a methyl group to yield inactive $6\text{-methylmercaptopurine}$.

UDP-Glucuronosyltransferases (UGTs)

A major superfamily of Phase II conjugating enzymes that catalyze glucuronidation, transferring glucuronic acid from UDP-glucuronic acid to xenobiotics and endogenous metabolites to enable biliary or renal excretion.

UGT1A1*28

A promoter polymorphism characterized by a $(TA)_7$ repeat expansion (instead of wild-type $(TA)_6$) in the $UGT1A1$ gene, leading to reduced enzyme expression, impaired glucuronidation, and heightened drug toxicity.

CYP1A2*1F

An allelic variant ($C > A$) of $CYP1A2$ associated with increased gene expression and hyper-metabolism of substrates such as clozapine, predisposing homozygous carriers ($*1F/*1F$) to low drug exposure and apparent treatment resistance.

Codeine

An opioid prodrug that requires bioactivation by $CYP2D6$ via O-demethylation into morphine ($5\text{--}10\%$ of administered dose) to achieve its primary analgesic effect.

CYP2D6 Variation in the Tiwi People

A pharmacogenomic finding in $N = 493$ Indigenous Tiwi individuals showing that $41\%$ have predicted impaired CYP2D6 metabolism ($29\%$ poor metabolizers, $12\%$ intermediate metabolizers), a rate substantially higher than global averages ($1\text{--}10\%$ poor metabolizers).

Schedule 4 Codeine Reclassification

An Australian regulatory action enacted on 1 February 2018 that reclassified all codeine-containing medications to Prescription Only Medicine (Schedule 4) due to public health and safety concerns regarding hyper-metabolizers and pediatric toxicity.

Selective Serotonin Reuptake Inhibitors (SSRIs)

First-line antidepressant drugs that inhibit the serotonin reuptake transporter (SERT) at the presynaptic membrane, primarily metabolized by $CYP2D6$ (fluoxetine, paroxetine, fluvoxamine) or $CYP2C19$ (citalopram, escitalopram, sertraline).

Tricyclic Antidepressants (TCAs)

Antidepressants comprising tertiary amines (amitriptyline, imipramine) demethylated by $CYP2C19$ into active secondary amines (nortriptyline, desipramine), both of which are subsequently hydroxylated into less active metabolites by $CYP2D6$.

HLA-B*15:02

An immune-complex allele prevalent in individuals of East Asian ancestry that strongly increases the risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) when prescribed carbamazepine ($\text{odds ratio} = 80.7$).

HLA-A*31:01

A genetic biomarker across diverse ancestral populations associated with carbamazepine-induced cutaneous adverse reactions, including SJS/TEN, DRESS, and maculopapular exanthema ($\text{odds ratio} = 5.65$).

P2Y12 Inhibitors

Antiplatelet agents (clopidogrel, prasugrel, ticagrelor) that prevent ADP from binding to the $P2Y_{12}$ receptor on platelets, thereby preventing glycoprotein IIb/IIIa activation, fibrinogen cross-linking, and platelet aggregation.

CYP2C19*2

A loss-of-function splicing variant ($c.681G>A$, $rs4244285$) of $CYP2C19$ that reduces clopidogrel bioactivation by $30\%$, conferring an elevated risk of major adverse cardiovascular events following percutaneous coronary intervention.

Metoprolol

A cardioselective $\beta_1$-adrenergic receptor blocker predominantly cleared via hepatic metabolism by $CYP2D6$, where poor metabolizers experience significantly increased drug exposure and risk of symptomatic bradycardia.

DPWG Metoprolol Recommendations

Clinical guidelines recommending that $CYP2D6$ poor metabolizers receive $25\%$ of the standard metoprolol dose and intermediate metabolizers receive $50\%$ of the dose, while ultra-rapid metabolizers receive titration up to $2.5\times$ the dose or an alternative agent.

Simvastatin

An HMG-CoA reductase inhibitor prodrug activated in the intestine and transported into the liver via OATP1B1, which carries an increased risk of severe myopathy in carriers of reduced-function transporter variants.

SLCO1B1 521T>C (*5)

A single nucleotide polymorphism in $SLCO1B1$ that impairs hepatic uptake of statins, elevating plasma statin concentrations and conferring a $17\text{-fold}$ increased risk of myopathy in homozygous carriers.

Warfarin Dosing Variability Factors

The multivariable factors contributing to therapeutic warfarin dose requirement, dominated by $VKORC1$ genotype (up to $25\%$), $CYP2C9$ genotype (up to $15\%$), clinical factors like age, sex, and weight ($10\text{--}20\%$), and unknown factors ($\ge 40\%$).

VKORC1

Vitamin K epoxide reductase complex subunit 1, the pharmacodynamic enzyme target inhibited by warfarin; common promoter variants increase warfarin sensitivity and necessitate significant dose reductions.

CYP2C9 (Warfarin Pharmacokinetics)

The Phase I cytochrome P450 enzyme responsible for clearing the more potent S-enantiomer of warfarin; decreased-function variants ($*2$ and $*3$) cause slower clearance, increased bleeding risk, and require substantial dose reductions.

International Normalized Ratio (INR)

A standardized prothrombin time ratio calculated as $\frac{PT_{\text{test}}}{PT_{\text{healthy reference}}}$ to monitor oral anticoagulation intensity, with a target therapeutic window typically between $2.0$ and $3.0$ for conditions such as atrial fibrillation.

Germline vs. Somatic Mutations

Inherited constitutional genetic variants present in all host tissues that influence baseline drug disposition and toxicity, contrasted with somatic acquired mutations confined strictly to neoplastic tumor tissue that govern oncogenic transformation.

Thiopurine Metabolic Pathway

The competing metabolic routes of azathioprine and $6\text{-MP}$, where bioactivation via HGPRT yields cytotoxic thioguanine nucleotides ($6\text{-TGMP} \rightarrow 6\text{-TGDP} \rightarrow 6\text{-TGTP}$) leading to apoptosis, while TPMT and NUDT15 serve as enzymatic checks that clear or dephosphorylate active metabolites.

NUDT15

Nudix hydrolase 15, an enzyme that dephosphorylates the active cytotoxic thiopurine metabolite $6\text{-TGTP}$ to $6\text{-TGMP}$; loss-of-function variants (notably $415C>T$) prevent thiopurine deactivation and cause severe, life-threatening myelosuppression.

5-Fluorouracil (5-FU)

A fluoropyrimidine antimetabolite chemotherapy agent that is bioactivated into cytotoxic fluoronucleotides to inhibit thymidylate synthase (TYMS) and disrupt RNA/DNA synthesis.

Dihydropyrimidine Dehydrogenase (DPD)

The rate-limiting catabolic enzyme encoded by the $DPYD$ gene responsible for degrading more than $80\%$ of administered $5\text{-FU}$ into inactive dihydrofluorouracil ($DHFU$).

DPYD*2A

A classic non-functional splicing variant ($c.1905+1G>A$) of the $DPYD$ gene associated with complete loss of DPD activity and severe or fatal fluoropyrimidine-induced toxicity in homozygous or compound heterozygous carriers.

Irinotecan Bioactivation and UGT1A1 Toxicity Pathway

The metabolic cascade wherein irinotecan is converted in the liver by carboxylesterases into the cytotoxic topoisomerase I inhibitor SN-38, whose detoxification to SN-38G is halted by the $UGT1A1*28$ variant, causing systemic SN-38 accumulation and severe neutropenia and diarrhea.

Imatinib

A small-molecule tyrosine kinase inhibitor that competitively binds the ATP-binding pocket of the chimeric BCR::ABL1 fusion oncoprotein in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive ALL.

BCR::ABL1 T315I

A point mutation in the kinase domain of BCR::ABL1 substituting threonine with isoleucine at residue 315, creating steric hindrance that completely abolishes imatinib binding and leads to profound secondary clinical resistance.

Endoxifen

The primary active metabolite of the selective estrogen receptor modulator (SERM) tamoxifen, produced via rate-limiting bioactivation by $CYP2D6$ and exhibiting up to a $100\text{-fold}$ higher affinity for estrogen receptors than the parent drug.

Methotrexate (MTX)

An antifolate chemotherapeutic agent that competitively inhibits dihydrofolate reductase (DHFR); its hepatic uptake is mediated by the OATP1B1 transporter encoded by $SLCO1B1$.

Rasburicase

A recombinant urate oxidase enzyme used to treat tumor lysis syndrome by catalyzing the oxidation of uric acid into soluble allantoin, generating hydrogen peroxide ($H_2O_2$) as an obligate metabolic byproduct.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

An X-linked enzymopathy resulting in depleted erythrocyte NADPH and reduced glutathione reserves, making red cells susceptible to catastrophic oxidative hemolysis upon exposure to rasburicase.

Allopurinol

A purine analog xanthine oxidase inhibitor used prophylactically to lower uric acid production in tumor lysis syndrome and gout.

HLA-B*58:01

An MHC class I allele strongly associated with allopurinol-induced severe cutaneous adverse reactions (SCARs), including SJS and TEN, for which CPIC guidelines designate allopurinol as strictly contraindicated.

Ondansetron

A $5\text{-HT}_3$ receptor antagonist antiemetic cleared by $CYP2D6$, $CYP3A4$, and $CYP1A2$; $CYP2D6$ ultra-rapid metabolizers clear the drug excessively fast and experience antiemetic failure, requiring alternative therapy such as granisetron.