3.1 Drug Absorption, Distribution, Metabolism, and Elimination (ADME)

3.1 Drug Absorption, Distribution, Metabolism, and Elimination (ADME)

Pharmacokinetics describes the quantitative time course of drug absorption, distribution, metabolism, and excretion (ADME)—frequently summarized as what the body does to the drug. A rigorous understanding of ADME principles is fundamental for evaluating therapeutic efficacy, anticipating drug-drug interactions, and adjusting dosage regimens in clinical pharmacy practice.

---

1. Physicochemical and Physiological Determinants of Drug Absorption

Drug absorption is the movement of an active pharmaceutical ingredient from its site of administration into the systemic circulation. For oral solid dosage forms, absorption requires drug dissolution into gastrointestinal fluids followed by transport across the gastrointestinal epithelial membrane.

Membrane Transport Mechanisms

+-----------------------------------------------------------------------------------+
|                             MEMBRANE PERMEATION ROUTES                            |
+-----------------------------------------------------------------------------------+
|  1. Passive Transcellular Diffusion  : Small, lipophilic, un-ionized molecules    |
|  2. Paracellular Transport           : Small, hydrophilic molecules (<200 Da)     |
|  3. Carrier-Mediated Influx (OATP)   : Facilitated diffusion / active transport   |
|  4. Efflux Transport (P-gp, BCRP)    : ATP-dependent active extrusion into lumen  |
|  5. Transcytosis / Endocytosis       : Macromolecules, peptides, nanoparticles    |
+-----------------------------------------------------------------------------------+

• Passive Transcellular Diffusion: The primary pathway for most lipophilic, low-molecular-weight drugs. The rate of diffusion across the apical membrane is governed by Fick's First Law of Diffusion:

$$\frac{dQ}{dt} = \frac{D \cdot A \cdot K \cdot (C_{\text{lumen}} - C_{\text{plasma}})}{h}$$

Where $dQ/dt$ represents the rate of drug transfer across the membrane, $D$ is the diffusion coefficient of the drug, $A$ is the functional surface area of the intestinal membrane (approximately $30\text{ m}^2$ in adults due to microvilli), $K$ is the lipid-water partition coefficient, $C_{\text{lumen}} - C_{\text{plasma}}$ is the concentration gradient, and $h$ is membrane thickness.

• The pH-Partition Hypothesis and Ionization Equivalence: Biological membranes are predominantly permeable to the lipid-soluble, un-ionized form of weak organic acids and bases. The extent of ionization is defined by the Henderson-Hasselbalch equations:

$$\text{For Weak Acids: } \text{pH} = \text{p}K_a + \log\left(\frac{[\text{Ionized Base (}A^-)]}{[\text{Un-ionized Acid (}HA)]}\right)$$ $$\text{For Weak Bases: } \text{pH} = \text{p}K_a + \log\left(\frac{[\text{Un-ionized Base (}B)]}{[\text{Ionized Conjugate Acid (}BH^+)]}\right)$$

Clinical Application (Ion Trapping): When a pH differential exists across biological membranes, basic drugs concentrate in acidic fluid compartments (e.g., breast milk, gastric secretions, prostatic fluid), whereas acidic drugs accumulate in basic compartments (e.g., systemic plasma relative to intracellular space).

Membrane Transporters in Absorption

• Efflux Transporters (ATP-Binding Cassette / ABC Family): P-glycoprotein (P-gp/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) are expressed on the apical surface of enterocytes. They utilize ATP hydrolysis to pump absorbed drugs back into the intestinal lumen, acting as a biochemical barrier to oral bioavailability.
  • P-gp Substrates: Digoxin, dabigatran etexilate, cyclosporine, tacrolimus, colchicine, loperamide.
  • P-gp Inhibitors: Clarithromycin, itraconazole, verapamil, amiodarone, quinidine, ritonavir. Co-administration increases substrate plasma concentrations, risking toxicity.
  • P-gp Inducers: Rifampin, carbamazepine, St. John's wort (Hypericum perforatum), phenytoin. Co-administration accelerates efflux, precipitating therapeutic failure.

---

2. Presystemic Extraction and First-Pass Metabolism

Before an orally administered drug reaches the systemic arterial circulation, it must pass sequentially through the gastrointestinal mucosa, the mesenteric venules, the hepatic portal vein, and the liver parenchymal tissue.

[Drug in GI Lumen] ---> [Enterocyte Uptake]
                               |
                               v
                  [Gut-Wall CYP3A4 / Phase II]  ---> Excreted / Inactive
                               |
                               v (Mesenteric / Portal Circulation)
                      [Hepatic First-Pass]
                               |
            +------------------+------------------+
            |                                     |
            v                                     v
  [Hepatic CYP450 / UGT]                 [Systemic Circulation]
  (High Extraction: Propranolol, Morphine)  (Active Drug Available)

• Intestinal First-Pass: Enterocytes contain substantial concentrations of CYP3A4/5 and Phase II enzymes. For instance, midazolam and cyclosporine undergo extensive pre-hepatic gut metabolism.
• Hepatic Extraction Ratio ($E_H$): Represents the fraction of drug entering the liver that is irreversibly removed during a single pass:

$$E_H = \frac{C_{\text{inflow}} - C_{\text{outflow}}}{C_{\text{inflow}}}$$

---

3. Apparent Volume of Distribution ($V_d$) and Tissue Binding

The apparent volume of distribution ($V_d$) is a proportionality constant that relates the total mass of drug in the body ($A_{\text{body}}$) to the measured drug concentration in plasma ($C_p$):

$$V_d = \frac{\text{Dose}_{\text{IV}}}{C_0} = \frac{A_{\text{body}}}{C_p}$$

Physiologically, $V_d$ is determined by the actual anatomical plasma volume ($V_p \approx 3\text{ L}$ in a $70\text{ kg}$ adult), extracellular water ($V_{\text{ECW}} \approx 14\text{ L}$), total body water ($V_{\text{TBW}} \approx 42\text{ L}$), and the fraction of unbound drug in plasma ($f_u$) relative to tissue ($f_{ut}$):

$$V_d = V_p + V_t \cdot \left(\frac{f_u}{f_{ut}}\right)$$

+------------------------------------------------------------------------------------+
|                   PHYSIOLOGICAL FLUID VOLUMES vs. DRUG EXAMPLES                    |
+------------------------------------------------------------------------------------+
|  Vd ~ 3 - 5 L (Vascular Pool)       : Heparin, Monoclonal Antibodies               |
|  Vd ~ 14 - 18 L (Extracellular Fluid): Aminoglycosides, Beta-Lactams, Vancomycin    |
|  Vd ~ 40 - 45 L (Total Body Water)  : Ethanol, Lithium, Theophylline               |
|  Vd >> 500 L (Extensive Tissue)     : Digoxin (~500 L), Amiodarone (~5000 L), TCAs |
+------------------------------------------------------------------------------------+

Plasma Protein Binding Dynamics

Only unbound (free) drug can cross biological membranes, interact with pharmacological receptors, and undergo glomerular filtration or hepatic biotransformation.

• Major Binding Macromolecules:

  • Albumin: Primarily binds neutral and acidic drugs (e.g., warfarin, phenytoin, valproic acid, methotrexate, salicylates, ceftriaxone).
  • $\alpha_1$-Acid Glycoprotein (AAG): An acute-phase reactant synthesized by hepatocytes that binds basic drugs (e.g., lidocaine, propranolol, verapamil, quinidine, tricyclic antidepressants). AAG concentrations rise markedly during inflammation, surgery, trauma, and malignancy.
  • Lipoproteins: Bind lipophilic basic compounds (e.g., cyclosporine, amiodarone).

• Hypoalbuminemia and the Winter-Tozer Correction: In conditions of reduced serum albumin (cirrhosis, nephrotic syndrome, critical illness, severe burns, protein malnutrition), the total measured serum concentration of highly bound drugs declines because clearance of total drug increases, but the absolute unbound concentration ($C_u = f_u \cdot C_{\text{total}}$) remains relatively constant. For phenytoin (which is normally $90\%$ protein-bound, $f_u = 0.10$), the Winter-Tozer equation estimates the normalized total concentration at normal albumin ($40\text{ g/L}$ or $4.0\text{ g/dL}$):

$$\text{In Conventional Units (Albumin in g/dL): } C_{\text{adj}} = \frac{C_{\text{obs}}}{(0.2 \cdot \text{Albumin}) + 0.1}$$ $$\text{In Canadian SI Units (Albumin in g/L): } C_{\text{adj}} = \frac{C_{\text{obs}}}{(0.02 \cdot \text{Albumin}) + 0.1}$$

ESRD Modification (CrCl $< 10\text{ mL/min}$): Due to reduced binding affinity from uremic toxins, the slope constant changes: $C_{\text{adj}} = C_{\text{obs}} / [(0.01 \cdot \text{Albumin}) + 0.1]$ (using $\text{g/L}$). Failure to correct leads to inappropriate dosage escalations and neurotoxicity.

---

4. Hepatic Biotransformation (Phase I and Phase II Reactions)

Metabolism converts lipophilic xenobiotics into more hydrophilic, water-soluble metabolites that can be excreted in urine or bile.

                   +-------------------------+
                   |     Parent Xenobiotic   |
                   +-------------------------+
                                |
                                v
    +-------------------------------------------------------+
    | Phase I (Functionalization: Oxidation, Hydrolysis)     |
    | Enzymes: CYP450, FMO, Alcohol Dehydrogenase, Esterase |
    +-------------------------------------------------------+
                                |
                                v
    +-------------------------------------------------------+
    | Phase II (Conjugation: Glucuronidation, Sulfation)    |
    | Enzymes: UGT, SULT, NAT, GST, TPMT                   |
    +-------------------------------------------------------+
                                |
                                v
                   +-------------------------+
                   |   Excretable Metabolite |
                   |       (Urine / Bile)    |
                   +-------------------------+

Cytochrome P450 Enzyme System

The CYP450 superfamily accounts for $>75\%$ of all drug biotransformations. The table below details high-yield enzymes for the PEBC examination:

Phase II Conjugation Enzymes and Pharmacogenetics

• UDP-Glucuronosyltransferases (UGTs): UGT1A1 conjugates bilirubin, SN-38 (irinotecan active metabolite), and dolutegravir. UGT2B7 metabolizes morphine to morphine-3-glucuronide (M3G, neurotoxic) and morphine-6-glucuronide (M6G, potent analgesic).
• N-Acetyltransferases (NAT1, NAT2): NAT2 metabolizes isoniazid, hydralazine, procainamide, and dapsone. "Slow acetylators" have elevated drug concentrations, predisposing them to peripheral neuropathy (isoniazid) and drug-induced lupus erythematosus (hydralazine, procainamide).
• Thiopurine S-Methyltransferase (TPMT): Inactivates 6-mercaptopurine and azathioprine. Patients homozygous for non-functional alleles accumulate thioguanine nucleotides, resulting in fatal bone marrow suppression unless the dose is reduced by $80-90\%$.

---

5. Renal and Non-Renal Clearance Pathways

Total systemic clearance ($CL$) is the sum of all organ-specific clearance mechanisms:

$$CL = CL_{\text{renal}} + CL_{\text{hepatic}} + CL_{\text{pulmonary}} + CL_{\text{other}}$$

Renal Clearance Mechanisms

$$\text{Renal Clearance } (CL_R) = (f_u \cdot GFR) + CL_{\text{secretion}} - \text{Rate of Reabsorption}$$

1. Glomerular Filtration: Passive filtration of unbound drugs across the fenestrated glomerular capillary membrane ($M_r < 60\text{ kDa}$). The maximum filtration clearance is $f_u \cdot GFR$.
2. Active Tubular Secretion: Energy-dependent transport from peritubular capillaries into the proximal tubular lumen via:
   • Organic Anion Transporters (OAT1/OAT3): Penicillins, cephalosporins, methotrexate, loop diuretics, probenecid. Interaction: Probenecid blocks OAT, dramatically increasing penicillin and methotrexate levels.
   • Organic Cation Transporters (OCT2 / MATE1/2-K): Metformin, cimetidine, trimethoprim. Interaction: Cimetidine and trimethoprim inhibit OCT2/MATE, elevating serum creatinine (pseudo-renal impairment) and metformin concentrations.
3. Passive Tubular Reabsorption: Lipophilic, un-ionized molecules are reabsorbed down concentration gradients in the distal tubule.
   • Urinary Alkalinization: Intravenous administration of sodium bicarbonate raises urine pH to $7.5 - 8.5$. For weak acids like salicylates ($\text{p}K_a \approx 3.0-3.5$) and methotrexate, ionization increases in alkaline urine, trapping them in the tubular lumen and accelerating renal excretion.

Biliary Clearance and Enterohepatic Recirculation

Drugs conjugated to glucuronide in the liver (e.g., ethinyl estradiol, mycophenolic acid, morphine, ezetimibe) are excreted into the bile and emptied into the duodenum. Intestinal bacterial flora produce $\beta$-glucuronidase, which hydrolyzes the conjugate, liberating the parent drug to be reabsorbed. Broad-spectrum antibiotics can suppress gut microflora, interrupting this cycle and lowering plasma drug levels.