Medicine and DDIs | For Doctors/Nurses/PharmDs
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Drug dosing as studied by research pharmacologists integrates pharmacokinetics and pharmacodynamics to achieve optimal therapeutic levels with minimal toxicity. Pharmacokinetics = absorption, distribution, metabolism, and excretion (ADME)—determines how long and how much of a drug remains active in systemic circulation. Metabolism occurs primarily in the liver, mediated by key cytochrome P450 (CYP) enzymes such as CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2, which together metabolize more than 80% of drugs. Conjugation pathways involving UGT (UDP-glucuronosyltransferases) and SULT (sulfotransferases) further enhance drug solubility for renal or biliary excretion.
Pharmacodynamics examines drug–receptor interactions, dose–response curves, and therapeutic windows. Precise dosing regimens are derived from preclinical modeling and human trials, guided by factors like bioavailability, clearance, half-life, and therapeutic index. Pharmacogenomics now refines dosing by identifying genetic polymorphisms; such as variations in CYP2C19 affecting clopidogrel activation or CYP2D6 influencing opioid metabolism.
The five most consumed global medicines illustrate these principles:
Acetaminophen (UGT1A6 metabolism) – analgesic/antipyretic. | 2 Ibuprofen (CYP2C9) – anti-inflammatory. | 3. Amoxicillin (non–CYP hepatic pathways) – antibiotic. | 4. Atorvastatin (CYP3A4) – cholesterol reduction. 5. Metformin (renal excretion via OCT2, MATE1 transporters) – glucose regulation.
Effective dosing merges enzymatic science, modeling, and individualized care to ensure efficacy and safety.
PHASE I AND II
PHASE I AND II
Phase I Metabolic Enzymes (Oxidation, Reduction, Hydrolysis)
Functionalization: Introduces or exposes polar groups (e.g., -OH) via oxidation, reduction, or hydrolysis to increase reactivity for Phase II.
Cytochrome P450 (CYP) superfamily CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 (most abundant, ~50% of drug metabolism), CYP3A5, CYP3A7 (fetal)
Flavin-containing monooxygenases (FMOs) FMO1, FMO2, FMO3 (major in adults), FMO4, FMO5
Monoamine oxidases MAO-A, MAO-B
Alcohol dehydrogenase (ADH)
Aldehyde dehydrogenase (ALDH)
Esterases / Amidases CES1, CES2, PON1, BChE
Phase II Metabolic Enzymes (Conjugation)
Conjugation: Adds large polar moieties (glucuronide, sulfate, glutathione) to Phase I products or parent drugs to enhance water solubility and excretion.
UDP-glucuronosyltransferases (UGTs) UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 (major for THC glucuronidation), UGT2B7 (highly active for opioids, cannabinoids)
Sulfotransferases (SULTs) SULT1A1, SULT1A3, SULT1B1, SULT1E1, SULT2A1
Glutathione S-transferases (GSTs) GSTA, GSTM1, GSTP1, GSTT1
N-acetyltransferases NAT1, NAT2
Methyltransferases COMT (catechol-O-methyltransferase), TPMT (thiopurine methyltransferase)
Key Notes for Pharmacists/Physicians:
CYP3A4, CYP2C9, CYP2D6 = primary for cannabinoid metabolism (THC → 11-OH-THC via CYP2C9/3A4).
UGT1A9 & UGT2B7 = major for glucuronidation of THC-COOH.
Genetic polymorphisms (e.g., CYP2D6 poor metabolizer) cause dosing variability.
Acetaminophen primarily undergoes Phase I metabolism before Phase II.
Metabolic Pathway (Simplified):
Metabolic Pathway (Simplified):
Phase I (Oxidation via CYP enzymes)
CYP2E1 (major), CYP1A2, CYP3A4 convert acetaminophen → NAPQI (N-acetyl-p-benzoquinone imine), a toxic reactive metabolite (~5–10% of dose).
Phase II (Conjugation for detoxification)
Glucuronidation (UGT1A1, UGT1A6, UGT1A9): ~50–60% → acetaminophen glucuronide
Sulfation (SULT1A1, SULT1A3): ~30% → acetaminophen sulfate
GSH conjugation (GSTs): NAPQI + glutathione → nontoxic mercapturate (excreted in urine)
Key Clinical Note:
Key Clinical Note:
At therapeutic doses, NAPQI is rapidly detoxified by glutathione.
In overdose, glutathione depletes → NAPQI binds liver proteins → hepatotoxicity.
Direct Phase II dominates (~90% of clearance), but Phase I is essential for forming the reactive intermediate.
TOP drug–drug interaction (DDI) checkers I mentioned:
Micromedex – https://www.micromedexsolutions.com/ micromedexsolutions.com+2Merative+2
UpToDate Lexidrug (formerly Lexicomp) – https://online.lexi.com/
25 Essential Pre-First-Pass Terms for Pharmacists & Physicians
25 Essential Pre-First-Pass Terms for Pharmacists & Physicians
Absorption – Drug entry from site of administration into systemic circulation.
Active transport – ATP-driven, carrier-mediated drug uptake.
ADME – Core processes: Absorption, Distribution, Metabolism, Excretion.
Bioequivalence – Comparable rate/extent of drug absorption between formulations.
Clearance (CL) – Volume of plasma fully cleared of drug per unit time.
Distribution – Drug dispersal from blood to tissues/organs.
Dose – Quantity of drug given at one administration.
Elimination – Permanent removal of drug via metabolism/excretion.
Enzyme induction – Upregulation of metabolic enzymes by inducers.
Enzyme inhibition – Blockade of enzyme activity reducing metabolism.
Half-life (t½) – Time for drug concentration to halve.
Ion trapping – pH-dependent ionization altering drug distribution.
Lipophilicity (LogP) – Measure of drug solubility in fat vs. water.
Metabolism – Biotransformation of drug into metabolites.
Passive diffusion – Non-energy-dependent movement down concentration gradient.
Pharmacodynamics (PD) – Biochemical/physiological effects of drugs.
Pharmacokinetics (PK) – Time course of drug in the body.
Plasma protein binding – Reversible binding to proteins like albumin.
Renal clearance – Drug removal via glomerular filtration, secretion, reabsorption.
Steady state – Equilibrium between dosing and elimination.
Therapeutic index – LD₅₀/ED₅₀; margin between efficacy and toxicity.
Volume of distribution (Vd) – Theoretical volume reflecting drug dispersion.
Zero-order kinetics – Constant elimination rate (e.g., high-dose ethanol).
First-order kinetics – Elimination proportional to drug concentration.
Route of administration – Delivery method (oral, IV, topical, etc.).
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