4.1: Principles of Pharmacokinetics (Absorption & Distribution)

4.1: Principles of Pharmacokinetics (Absorption & Distribution)

Pharmacokinetics describes the quantitative relationship between the administered dose of a drug and its plasma concentration over time, representing "what the body does to the drug". This process is governed by the principles of Absorption, Distribution, Metabolism, and Elimination (ADME). This section focuses on the mechanisms and variables governing how drugs enter the body and distribute through tissues.

Mechanisms of Drug Absorption

Absorption is the process by which a drug proceeds from its site of administration to the systemic circulation. For a drug to be absorbed, it must cross biological membranes, which are primarily phospholipid bilayers.

1. Passive Diffusion

Passive diffusion is the primary mechanism of absorption for the vast majority of clinical drugs. It requires no energy (ATP) and is driven by a concentration gradient. The rate of passive diffusion is described 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 function of molecular size and membrane resistance).
• $A$ is the surface area available for absorption (e.g., the small intestine has a massive surface area of $\approx 200 \text{ m}^2$ due to microvilli, making it the primary site of absorption even for drugs that are ionized in its neutral-to-basic environment).
• $K$ is the lipid-water partition coefficient (lipophilicity; high log P values favor diffusion).
• $C_{\text{out}} - C_{\text{in}}$ is the concentration gradient across the membrane.
• $h$ is the membrane thickness.

The pH-Partition Hypothesis and Ionization

Most drugs are weak electrolytes (either weak acids or weak bases) that exist in equilibrium between ionized (polar, water-soluble) and non-ionized (non-polar, lipid-soluble) forms. Only the non-ionized form can readily cross cell membranes by passive diffusion. The ratio of ionized to non-ionized drug at a given pH is determined by the Henderson-Hasselbalch equations:

• For a weak acid (e.g., aspirin, $\text{p}K_a \approx 3.5$): $\text{pH} = \text{p}K_a + \log\left(\frac{[\text{Ionized } A^-]}{[\text{Non-ionized } HA]}\right)$
• For a weak base (e.g., propranolol, $\text{p}K_a \approx 9.2$): $\text{pH} = \text{p}K_a + \log\left(\frac{[\text{Non-ionized } B]}{[\text{Ionized } BH^+]}\right)$

Exam Trap: While aspirin is non-ionized in the highly acidic stomach (pH 1–2) and theoretically absorbed there, the bulk of aspirin absorption still occurs in the duodenum/jejunum due to the small intestine's enormous surface area and high blood perfusion, which rapidly sweep the absorbed drug away to maintain the concentration gradient.

2. Carrier-Mediated Transport

Some drugs mimic endogenous substances and cross membranes via carrier proteins:

• Active Transport: Requires ATP and can move drugs against a concentration gradient (e.g., levodopa crossing the blood-brain barrier via the L-type amino acid transporter). Active transport is saturable, susceptible to competitive inhibition, and temperature-dependent.
• Facilitated Diffusion: Carrier-mediated but does not require energy, moving drugs down their concentration gradient (e.g., organic cation transporters for metformin).

The Role of P-glycoprotein (P-gp)

P-glycoprotein (P-gp), encoded by the ABCB1 gene, is an ATP-dependent efflux pump located on the apical membrane of enterocytes, renal proximal tubules, hepatocytes, and brain capillary endothelial cells. It pumps substrates back out of the cell.

• Clinical Significance: Digoxin is a classic P-gp substrate. If a patient is taking digoxin and is prescribed a P-gp inhibitor (e.g., verapamil, amiodarone, clarithromycin), P-gp efflux in the gut wall is reduced. This significantly increases digoxin absorption and plasma levels, posing a high risk of digitalis toxicity (symptoms: bradycardia, yellow-green visual halos, nausea). Conversely, P-gp inducers (e.g., rifampicin, St John's Wort) decrease digoxin absorption.

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Bioavailability (F)

Bioavailability ($F$) is the fraction of an administered dose of drug that reaches the systemic circulation in an active, unchanged form. By definition, the bioavailability of an intravenously administered drug is 1.0 (or 100%). For extravascular routes (e.g., oral, subcutaneous, intramuscular), bioavailability is less than 1.0 ($F < 1$) and is calculated as:

$F = \frac{\text{AUC}_{\text{extravascular}}}{\text{AUC}_{\text{IV}}} \cdot \frac{\text{Dose}_{\text{IV}}}{\text{Dose}_{\text{extravascular}}}$

Factors Limiting Bioavailability

1. Presystemic Elimination (First-Pass Hepatic/Gut Wall Metabolism): After oral ingestion, drugs are absorbed into the portal vein and pass through the liver before reaching systemic circulation. Highly extracted drugs undergo extensive first-pass metabolism, dramatically reducing $F$.
   • High First-Pass Drugs: Morphine, glyceryl trinitrate (GTN), propranolol, verapamil, lignocaine/lidocaine.
   • Clinical Application: GTN is administered sublingually (or transdermally) to bypass the portal circulation, allowing direct absorption into the superior vena cava and providing rapid therapeutic effect. If swallowed, GTN's bioavailability is $< 1%$.
   • Gut Wall Metabolism: CYP3A4 is highly expressed in the intestinal mucosa. Grapefruit juice selectively inhibits intestinal CYP3A4, which increases the bioavailability of oral CYP3A4 substrates (e.g., felodipine, simvastatin, ciclosporin) without affecting their systemic clearance.
2. Gastrointestinal Factors:
   • Gastric pH: Drugs like ketoconazole, itraconazole, and atazanavir require an acidic environment to dissolve. Co-administration with proton pump inhibitors (PPIs) or $H_2$-receptor antagonists increases gastric pH, preventing dissolution and therapeutic failure.
   • Gastric Motility: Prokinetic agents (e.g., metoclopramide) accelerate gastric emptying, increasing the rate of absorption of drugs like paracetamol. Anticholinergics (e.g., atropine, hyoscine) delay emptying, slowing absorption.
   • Chemical/Physical Interactions (Complexation): Tetracycline antibiotics (doxycycline, minocycline) and fluoroquinolones (ciprofloxacin, norfloxacin) chelate with multivalent cations ($Ca^{2+}$, $Mg^{2+}$, $Al^{3+}$, $Fe^{2+}$, $Zn^{2+}$) present in dairy products, antacids, and iron supplements. This forms insoluble complexes that cannot cross the intestinal wall, rendering the antibiotic ineffective. These must be spaced (e.g., take antibiotic 2 hours before or 4–6 hours after the cation).

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Volume of Distribution (Vd)

The apparent Volume of Distribution ($V_d$) is a theoretical parameter that relates the amount of drug in the body to the measured concentration in the plasma at time zero ($C_0$):

$V_d = \frac{\text{Amount of drug in the body (Dose)}}{C_0}$

$V_d$ does not represent a physical anatomical space but reflects the extent of tissue distribution.

Factors Influencing Vd

• Lipophilicity and Charge: Lipophilic, uncharged drugs easily cross membranes and partition into adipose and tissue compartments, resulting in a large $V_d$ (e.g., amiodarone $\approx 70 \text{ L/kg}$). Hydrophilic, polar, or highly ionized drugs tend to remain in the vascular compartment, resulting in a small $V_d$ (e.g., gentamicin $\approx 0.25 \text{ L/kg}$).
• Molecular Size: Very large molecules (e.g., heparin, monoclonal antibodies) are physically restricted to the vascular space, yielding a very low $V_d$ ($\approx 0.05-0.1 \text{ L/kg}$).
• Protein Binding: High plasma protein binding keeps the drug in the blood (low $V_d$). High tissue binding (e.g., digoxin binding to skeletal muscle $\text{Na}^+/\text{K}^+$-ATPase) pulls the drug out of blood (large $V_d$).

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Plasma Protein Binding

In the circulation, drugs exist in an equilibrium between bound and unbound (free) forms.

Major Binding Proteins

1. Albumin: Primarily binds acidic and neutral drugs. Normal range: 35–50 g/L.
   • Examples: Phenytoin, warfarin, valproate, NSAIDs, salicylic acid.
2. $\alpha_1$-Acid Glycoprotein (AAG): Primarily binds basic and lipophilic drugs.
   • Examples: Lignocaine/lidocaine, propranolol, tricyclic antidepressants, methadone.
   • Exam Note: AAG is an acute-phase reactant. During states of trauma, infection, inflammation, or myocardial infarction, AAG levels rise, causing a decrease in the free (active) fraction of basic drugs.

Clinical Significance of Protein Binding

Only the free (unbound) drug can cross cell membranes, interact with pharmacological receptors to exert an effect, and undergo glomerular filtration or hepatic metabolism.

• Displacement Interactions: When two highly protein-bound drugs (typically $>90%$ bound) compete for the same albumin binding sites, one drug may displace the other.
  • Phenytoin and Valproate: Sodium valproate displaces phenytoin from albumin binding sites and simultaneously inhibits its hepatic metabolism. The free fraction of phenytoin increases. A patient may display signs of phenytoin toxicity (e.g., nystagmus, ataxia) even if their reported total phenytoin level is within the standard therapeutic range (10–20 mg/L or 40–80 micromol/L).
• Hypoalbuminaemia: In conditions such as liver cirrhosis, nephrotic syndrome, malnutrition, pregnancy, or in frail elderly patients, plasma albumin levels fall below 35 g/L. This increases the free fraction ($f_u$) of highly bound drugs like phenytoin. Standard lab assays measure total concentration (bound + free). In hypoalbuminaemia, the measured total concentration will underestimate the active free concentration.
  • To prevent toxic dose escalations, clinicians must calculate the corrected phenytoin concentration using the Sheiner-Tozer Equation (adjusted for Australian g/L albumin units): $C_{\text{corrected}} = \frac{C_{\text{measured}}}{0.02 \cdot \text{Albumin (g/L)} + 0.1}$ If albumin is measured in g/dL, the multiplier is 0.2 instead of 0.02.
  • Worked Example: A patient with liver disease has a serum albumin of 20 g/L. The lab reports a total phenytoin level of 8 mg/L. $C_{\text{corrected}} = \frac{8.0}{0.02 \cdot 20 + 0.1} = \frac{8.0}{0.4 + 0.1} = \frac{8.0}{0.5} = 16 \text{ mg/L}$ The corrected value of 16 mg/L is therapeutic, whereas the raw value of 8 mg/L falsely suggested a subtherapeutic level. Increasing the dose based on the raw value could induce toxicity.

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Physiological Barriers to Distribution

1. The Blood-Brain Barrier (BBB)

The BBB restricts the entry of polar substances into the central nervous system. It consists of:

• Continuous capillary endothelial cells with tight junctions (zonula occludens).
• Astrocytic foot processes surrounding the capillaries.
• P-gp efflux transporters that actively pump foreign molecules back into the blood.

Clinical Context: Lipophilic beta-blockers (e.g., propranolol, metoprolol) cross the BBB by passive diffusion, causing CNS side effects such as vivid dreams, nightmares, and fatigue. In contrast, hydrophilic beta-blockers (e.g., atenolol) do not cross the BBB, making them preferred alternatives if CNS side effects occur. Meningitis: Inflammation of the meninges disrupts the tight junctions of the BBB. This allows polar antibiotics like benzylpenicillin and ceftriaxone to penetrate the CNS in therapeutic concentrations, whereas they are excluded under normal conditions.

2. The Placental Barrier and Breast Milk

• Placental Transfer: Lipophilic, uncharged, small molecules cross the placenta easily. Highly charged, large molecules (e.g., heparin, insulin) do not cross. Hence, low molecular weight heparin (LMWH, e.g., enoxaparin) or unfractionated heparin is the anticoagulant of choice during pregnancy in Australia, as warfarin is teratogenic.
• Breast Milk Accumulation: Breast milk has a slightly lower pH than maternal plasma (milk pH $\approx 7.2$ vs. plasma pH 7.4). Weakly basic drugs (e.g., codeine, morphine, beta-blockers) cross into breast milk in their non-ionized state. Once in the acidic milk, they become ionized and cannot easily diffuse back into the maternal circulation. This is known as ion trapping, resulting in a high milk-to-plasma (M/P) ratio.