Pharmacokinetics: Metabolism, Excretion, Bioavailability & Half-Life

Metabolism

• Converts lipophilic drugs → more hydrophilic forms to enable removal.
• Principal site: liver (microsomal enzymes).
• Two phases:
  1. Phase I: functionalisation via cytochrome $P450$ → alters solubility/activity.
  2. Phase II: conjugation with polar molecule → highly water-soluble metabolite.

Hepatic First-Pass Effect

• All orally-taken drugs enter liver via hepatic portal vein before systemic circulation.
• Extensive metabolism here ↓ available dose.
• Example: Glycerol trinitrate – $\approx96\%$ destroyed on first pass.
• High first-pass → prefer non-oral routes (e.g., sublingual).

Excretion

• Removes drug/metabolites from body.
• Major route: kidneys (filtration → reabsorption → secretion → urine).
• Other routes: bile/faeces, breath, saliva, sweat, breast milk.

Drug Clearance

• Sum of metabolism + excretion rates across all organs.
• Determines overall elimination.

Dose Adjustment in Impaired Function

• Hepatic disease ↓ metabolism → prolongs drug action.
• Renal disease ↓ excretion.
• Usual response: reduce dose and/or extend dosing interval.

Bioavailability (F)

• Fraction of administered dose reaching systemic circulation unchanged.
• Influenced by: absorption losses + hepatic first-pass.
• Non-oral routes (IV, sublingual, buccal, rectal, inhalation) bypass first-pass → $\approx100\%$ F.
• Example: Morphine
  • IV: $100\%$ F → give $10\,\text{mg}$ for $10\,\text{mg}$ target dose.
  • Oral: $30\%$ F → need $\approx30\,\text{mg}$ to deliver same $10\,\text{mg}$ systemically.

Drug Half-Life ($t_{1/2}$)

• Time for plasma concentration to fall by $50\%$.
• Example: $100\,\text{mg·L}^{-1} \to 50\,\text{mg·L}^{-1}$ in $4\,\text{h}$ ⇒ $t_{1/2}=4\,\text{h}$.
• Elimination usually complete after $4$–$5\,t_{1/2}$.
• Overdose ↑ initial concentration → more half-lives needed.

Steady State & Dosing

• Goal: maintain plasma level ≥ minimum effective concentration.
• Steady state reached after $4$–$5\,t_{1/2}$ with regular dosing.
• Long $t_{1/2}$ (e.g., $48\,\text{h}$): days to steady state (e.g., antidepressants).
• Short $t_{1/2}$ (e.g., $2\,\text{h}$): steady state within hours.