Pharmacokinetics: Drug Absorption, Distribution, Metabolism, and Excretion (ADME)

Pharmacokinetics (PK) describes what the body does to a drug — absorption, distribution, metabolism, and excretion (ADME). Pharmacodynamics (PD) describes what the drug does to the body. The VTNE tests both, but the ADME framework is the more frequently examined because species differences in metabolism explain why a drug safe in dogs is lethal in cats (acetaminophen) and why dose intervals differ across species.

Absorption

Absorption is the movement of drug from the site of administration into systemic circulation. Rate and extent (bioavailability) depend on route, drug formulation, and patient factors:

• Intravenous (IV) — 100% bioavailability by definition (no absorption barrier); fastest onset; preferred for emergencies and precise titration (anesthesia induction, CRI analgesia).
• Intramuscular (IM) — aqueous solutions absorbed within 10 to 30 minutes; oil-based depots (e.g., penicillin G benzathine) extend duration for days; dependent on muscle blood flow — shock and dehydration slow absorption.
• Subcutaneous (SQ/SC) — slower than IM; useful for sustained absorption (insulin, fluids, vaccines); affected by peripheral perfusion.
• Oral (PO) — most convenient and least reliable; subject to first-pass hepatic metabolism (a fraction of drug is metabolized in the liver before reaching systemic circulation); gastric pH, presence of food, vomiting, and GI transit time all alter bioavailability. Cats have higher gastric pH than dogs and may absorb acid-labile drugs differently.
• Transdermal — fentanyl patches, selegiline, methimazole in cats; slow and variable onset; cats' thinner skin and grooming behavior complicate dosing.
• Topical/local — otic, ophthalmic, dermal; minimal systemic absorption unless barrier compromised.

The pH-partition hypothesis predicts absorption: non-ionized (lipid-soluble) drug crosses membranes; ionized (water-soluble) drug stays in compartment. Weak acids (aspirin, penicillins, barbiturates) are non-ionized in acidic stomach and ionized in alkaline small intestine; weak bases (opioids, local anesthetics, antihistamines) are non-ionized in alkaline environments. Drug interactions that alter gastric pH (omeprazole, H2 blockers) can shift absorption of pH-dependent drugs.

Distribution

Once in plasma, drugs distribute based on:

1. Protein binding — acidic drugs bind albumin; basic drugs bind alpha-1-acid glycoprotein. Only free (unbound) drug is pharmacologically active and available for metabolism and excretion. Hypoalbuminemia (liver disease, nephrotic syndrome, malnutrition) increases free fraction of highly protein-bound drugs (phenobarbital, NSAIDs) — reduce dose.
2. Lipid solubility — highly lipophilic drugs (diazepam, barbiturates, anesthetics) cross the blood-brain barrier readily; this is why propofol produces rapid induction and redistribution.
3. Volume of distribution (Vd) — describes apparent volume a drug occupies; high Vd concentrates in tissues (digoxin); low Vd stays in plasma (gentamicin).
4. Special barriers — blood-brain barrier (excludes ionized, protein-bound, large molecules); placental barrier (most drugs cross — teratogenic risk); mammary gland (drug residues in milk — relevant for lactating animals and food-animal withdrawal times).

Species-specific distribution notes: cats have less body fat than dogs on average, so lipid-soluble drugs redistribute less; neonates have higher total body water and lower albumin (about 60 percent of adult levels in the first weeks), so loading doses of water-soluble drugs are higher per kg but free fractions of bound drugs are higher.

Metabolism

Metabolism (biotransformation) converts lipophilic drugs to more hydrophilic metabolites for excretion — usually inactivating the drug, but occasionally activating prodrugs (enrofloxacin to ciprofloxacin; prednisone to prednisolone in the liver). Two phases:

• Phase I — oxidative, reductive, hydrolytic reactions (mostly cytochrome P450 family). Adds or unmasks a functional group. Cats have significantly lower hepatic glucuronidation (a Phase II pathway) than dogs — the feline UGT1A6 and UGT2B7 isoforms that conjugate phenolic drugs are minimally expressed. This single species difference explains why acetaminophen (paracetamol) is fatal to cats: acetaminophen is metabolized in Phase I to NAPQI (a reactive quinone imine); in dogs and humans, glutathione conjugates NAPQI via glucuronidation and sulfation and excretes it. In cats, depleted glutathione and weak glucuronidation allow NAPQI to accumulate, causing methemoglobinemia, Heinz body anemia, and hepatic necrosis. Even one 325-mg tablet is lethal to an average cat. N-acetylcysteine (NAC) is the antidote — it replenishes glutathione and directly conjugates NAPQI.
• Phase II — conjugation (glucuronidation, sulfation, acetylation, glutathione). Cats favor sulfation over glucuronidation; dogs have both pathways; pigs lack sulfate conjugation for some substrates. This is why carprofen is well-tolerated in dogs (mostly biliary excretion, minimal Phase II) but is used cautiously in cats (only the injectable form is approved in cats in the U.S., with strict dosing intervals).

Cytochrome P450 inducers (phenobarbital, rifampin, glucocorticoids) speed metabolism of co-administered drugs, reducing their effect; inhibitors (chloramphenicol, cimetidine, fluoxetine, ketoconazole, itraconazole) slow metabolism, increasing effect or toxicity. Chloramphenicol inhibits P450 and dramatically prolongs phenobarbital half-life in dogs — a classic VTNE drug-drug interaction.

Excretion

Excretion removes drug or metabolite from the body. The kidney is the primary route for water-soluble drugs and metabolites:

• Glomerular filtration — passive; only free (unbound) drug filtered; protein-bound drug retained in plasma.
• Tubular secretion — active transport (OAT for acids, OCT for bases); competition causes interactions (probenecid blocks penicillin secretion, prolonging its half-life — useful therapeutically).
• Tubular reabsorption — passive, pH-dependent; acidic urine (carnivores) reabsorbs weak acids (extends half-life of aspirin, barbiturates); alkaline urine (herbivores, post-IV bicarbonate) reabsorbs weak bases. Forced alkaline diuresis with sodium bicarbonate enhances salicylate (aspirin) and barbiturate excretion in toxicosis.

Biliary excretion: some drugs (erythromycin, ampicillin, some NSAIDs) are excreted in bile; enterohepatic recirculation prolongs half-life when intestinal bacteria deconjugate the metabolite and it is reabsorbed — this is why repeated activated charcoal every 4 to 8 hours enhances elimination of drugs that undergo enterohepatic recirculation (tricyclic antidepressants, phenobarbital, theobromine).

Renal disease reduces clearance of renally excreted drugs (aminoglycosides, penicillins, furosemide, gabapentin, digoxin) — adjust dose or interval. Hepatic disease reduces clearance of hepatically cleared drugs (diazepam, phenobarbital, NSAIDs, lidocaine); cats with hepatic lipidosis have prolonged recovery from benzodiazepines. Always consider the interaction between organ function and clearance route before administering drugs to a patient with compromised liver or kidney function.