Section 2.2: Drug ADME (Absorption, Distribution, Metabolism, Excretion)

Section 2.2: Drug ADME (Absorption, Distribution, Metabolism, Excretion)

Introduction to Pharmacokinetics

Pharmacokinetics (PK) describes the quantitative relationship between the dose of a drug and its plasma concentrations over time. The physiological processes governing PK are grouped into the acronym ADME: Absorption, Distribution, Metabolism, and Excretion. Mastery of ADME is vital for passing the SPLE, as it forms the basis for therapeutic drug monitoring (TDM), managing drug-drug interactions, and adjustment of dosing regimens in renal and hepatic impairment.

Drug Absorption: Passive vs. Active

Absorption is the process by which a drug travels from its site of administration to the systemic circulation.

• Passive Diffusion: The most common mechanism. It does not require energy or carrier proteins and is driven solely by a concentration gradient. It is governed by Fick's Law of Diffusion: $\text{Rate of Diffusion} = \frac{D \cdot A \cdot K \cdot (C_{\text{out}} - C_{\text{in}})}{h}$ where $D$ is the diffusion coefficient, $A$ is the membrane surface area, $K$ is the lipid-water partition coefficient, and $h$ is membrane thickness. Passive diffusion is saturable-free and highly dependent on the drug's lipophilicity and ionization state.
• Active Transport: Requires carrier proteins and energy in the form of ATP. It allows drugs to move against their concentration gradient. This process is highly specific, saturable, and subject to competitive inhibition by other substrates. Active transporters include solute carriers (SLCs) like organic anion transporting polypeptides (OATPs) which absorb statins and organic cation transporters (OCTs).
• Efflux Pumps (P-glycoprotein): P-glycoprotein (P-gp), encoded by the ABCB1 gene, is an ATP-binding cassette transporter located on the apical membrane of enterocytes, renal tubule cells, hepatocytes, and endothelial cells of the blood-brain barrier. P-gp acts as a defense mechanism by actively pumping absorbed drugs back into the intestinal lumen, limiting their bioavailability. Digoxin, cyclosporine, and dabigatran are major substrates of P-gp. Inhibitors of P-gp (e.g., verapamil, amiodarone) will increase their absorption, while inducers (e.g., rifampin) will reduce it.

Volume of Distribution and Plasma Protein Binding

Once a drug enters the bloodstream, it distributes to various tissues. The extent of distribution is described by the Apparent Volume of Distribution ($V_d$): $V_d = \frac{\text{Total Amount of Drug in Body}}{\text{Plasma Drug Concentration } (C_0)}$ $V_d$ is a theoretical volume and does not represent an actual anatomical volume.

• Low $V_d$ (< 5 L or ~0.07 L/kg): Indicates that the drug is largely confined to the plasma. This is typical for drugs that are highly polar, large, or extensively bound to plasma proteins (e.g., heparin, warfarin).
• High $V_d$ (> 42 L or ~0.6 L/kg): Indicates that the drug distributes extensively into tissues, meaning the concentration in plasma is very low. This is typical for highly lipophilic drugs (e.g., chloroquine, amiodarone, digoxin) or drugs that bind strongly to tissue proteins (e.g., skeletal muscle).

Plasma Protein Binding: Drugs in circulation exist in an equilibrium between bound and unbound states. Only the free (unbound) drug can interact with receptors, cross membranes, and undergo metabolism or excretion.

• Albumin: The primary plasma protein that binds acidic drugs (e.g., NSAIDs, warfarin, phenytoin).
• Alpha-1 Acid Glycoprotein (AAG): Binds basic drugs (e.g., propranolol, lidocaine, tricyclic antidepressants).

Clinical Significance: For highly protein-bound drugs (>90% bound), co-administration of another drug that competes for the same binding site can lead to a displacement interaction. For example, sulfonamides can displace warfarin or bilirubin from albumin. This causes a transient spike in the free (active) concentration of the displaced drug, potentially leading to toxic effects (e.g., severe bleeding or kernicterus in neonates) before the liver and kidneys clear the excess free drug and re-establish a new steady-state equilibrium.

Drug Metabolism: Phase I and Phase II

Metabolism converts lipophilic drugs into polar, water-soluble metabolites that can be easily excreted. It occurs primarily in the liver.

Phase I Reactions (Functionalization)

Phase I reactions introduce or expose a polar functional group ($-OH$, $-NH_2$, $-SH$) on the molecule through oxidation, reduction, or hydrolysis. The primary enzyme system responsible is the Cytochrome P450 (CYP450) superfamily located in the smooth endoplasmic reticulum of hepatocytes.

• CYP3A4: The most abundant isoform, metabolizing over 50% of all clinically used drugs (e.g., statins, calcium channel blockers, macrolides).
• CYP2D6: Responsible for metabolizing codeine (converting it to its active form, morphine), beta-blockers, and antidepressants. It exhibits significant genetic polymorphism, dividing the population into poor, extensive, and ultra-rapid metabolizers.
• CYP2C9: Metabolizes S-warfarin, phenytoin, and most NSAIDs. Polymorphisms in CYP2C9 require lower doses of warfarin to avoid bleeding.

Phase II Reactions (Conjugation)

Phase II reactions attach a large polar endogenous molecule to the drug or its Phase I metabolite, making it highly water-soluble and generally pharmacologically inactive.

• Glucuronidation: Mediated by UDP-glucuronosyltransferases (UGTs). The most common Phase II pathway (e.g., acetaminophen conjugation).
• Acetylation: Mediated by N-acetyltransferases (NAT1 and NAT2). NAT2 polymorphisms split patients into "fast" or "slow" acetylators, which affects the toxicity and half-life of drugs like isoniazid, hydralazine, and procainamide (slow acetylators are at higher risk of isoniazid-induced peripheral neuropathy and hydralazine-induced lupus).
• Sulfation: Mediated by sulfotransferases (SULTs).
• Glutathione Conjugation: Mediated by glutathione S-transferases (GSTs); critical for neutralizing electrophilic toxic metabolites like NAPQI.

Enzyme Induction and Inhibition

• Enzyme Inhibitors: Block Cytochrome P450 enzyme activity. This decreases the metabolism of co-administered substrate drugs, raising their plasma levels and risking toxicity. Common inhibitors include ketoconazole, erythromycin, clarithromycin, cimetidine, amiodarone, and grapefruit juice.
• Enzyme Inducers: Stimulate the synthesis of more CYP450 enzymes. This increases the metabolism of substrate drugs, lowering their plasma levels and risking therapeutic failure. Common inducers include rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's wort.

Renal and Biliary Clearance

Renal Clearance

Renal excretion is the primary pathway for eliminating water-soluble drugs. It is the net result of three processes:

1. Glomerular Filtration: Passive process. Only free (unbound) drug is filtered through the glomerulus. The glomerular filtration rate (GFR) dictates this clearance.
2. Active Tubular Secretion: Energy-dependent carrier-mediated process occurring in the proximal tubule. Transporters actively secrete organic acids and bases into the tubule lumen, even if they are protein-bound.
3. Passive Tubular Reabsorption: Occurs in the distal tubule. Lipophilic, un-ionized drugs are passively reabsorbed back into the systemic circulation.
   • Ion Trapping in Renal Excretion: Urine pH can be manipulated to promote drug excretion. For weak acid overdoses (e.g., aspirin), administering sodium bicarbonate alkalizes the urine. At basic pH, the weak acid ionizes ($A^-$), preventing reabsorption and accelerating clearance. For weak base overdoses (e.g., amphetamines), ammonium chloride can be used to acidify the urine, trapping the base in its ionized form ($BH^+$).

Biliary Clearance

Many polar drugs and conjugates (molecular weight > 300-500 Da) are actively secreted by hepatocytes into the bile and excreted in feces.

• Enterohepatic Recirculation: Glucuronide conjugates excreted in bile reach the intestine, where bacterial beta-glucuronidase enzymes hydrolyze the conjugate back into the active parent drug. The free lipophilic drug is then reabsorbed back into the portal circulation. This process creates a secondary peak in plasma drug concentration and significantly prolongs the drug's half-life (e.g., ezetimibe, oral contraceptives). If a patient is prescribed broad-spectrum antibiotics, the intestinal flora is depleted, preventing hydrolysis and leading to decreased levels of the recirculated drug (a classic mechanism for antibiotic-induced oral contraceptive failure).