3 Clinical psychopharmacology3.2 Pharmacokinetics
3.2.1.1 Absorption, distribution, metabolism and elimination
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Written by Resident Doctor Committee · Published
Pharmacokinetic terms
Pharmacokinetics is the study of absorption, distribution, metabolism and elimination (ADME), which together make up the body's handling of a drug.
Pharmacodynamics is the study of the drug's action at its target, and is distinct from pharmacokinetics.
Therapeutic index is the ratio of toxic dose to effective dose.
Therapeutic index | Examples |
|---|---|
Wide | Sertraline, gabapentin, benzodiazepines |
Narrow | Amitriptyline, phenobarbital, carbamazepine, lithium |
Absorption
Absorption is the movement of a drug from where it was given into the circulation, and intravenous (IV) dosing bypasses it.
Absorption depends on the drug, its formulation and the absorption site. Elimination acts only on drug already absorbed, so it cannot change absorption.
Passive diffusion across a lipid membrane works best for molecules that are small, lipid soluble and uncharged.
Tablets must release dissolved drug before uptake, and smaller particle size speeds dissolution and raises absorption.
Low lipid solubility, P-glycoprotein efflux, rapid transit and poor gut blood flow all reduce absorption.
pH alters dissolution and the un-ionised fraction, although ionised drugs can still be well absorbed.
The small intestine is the main site of absorption of oral psychotropics, because its surface area and contact time outweigh the pH-partition argument for gastric uptake. The stomach contributes little.
Gastric emptying affects how soon absorption begins.
Vomiting, diarrhoea, malabsorption and bariatric surgery can all alter exposure.
Oral bioavailability of individual drugs
Food effects are specific to each product.
Drug | Bioavailability | Reason | Practical point |
|---|---|---|---|
Lurasidone | 9 to 19% fasting | Poorly water soluble | A meal of about 350 kcal or more raises absorption two to three times, so it must be taken with food |
Amisulpride | About 48% | Polar molecule, incompletely absorbed; only about 4% metabolised | The kidneys clear it unchanged |
Asenapine (sublingual) | About 35% | Bypasses the portal circulation and first-pass loss | Drinking soon afterwards lowers exposure |
Aripiprazole | About 87% | Unaffected by food | Half-life about 75 hours, so two weeks to steady state |
Chlorpromazine | About a third or less | First-pass loss in gut wall and liver | Lowest of the common psychotropics |
With lurasidone, the meal roughly doubles total exposure and triples the peak concentration.
Aripiprazole has a longer half-life in poor cytochrome P450 2D6 (CYP2D6) metabolisers.
Bioavailability and first-pass metabolism
Bioavailability (F) is the fraction of a dose that reaches the systemic circulation unchanged.
IV dosing has bioavailability of 100% (F = 1) by definition, so it is the reference for absolute bioavailability.
Absolute bioavailability = dose-normalised area under the concentration-time curve (AUC) after the test route / dose-normalised AUC after an IV dose.
Oral bioavailability is set before the drug reaches the systemic circulation, by the fraction absorbed and the fraction surviving first-pass extraction. Volume of distribution acts afterwards and does not change it.
First-pass (presystemic) metabolism is the loss of an oral dose to metabolism in the gut wall and liver before it reaches the systemic circulation, even after complete absorption.
First-pass loss happens in the gut wall and liver, not the kidney or lungs, and it spares an IV dose.
Non-oral routes generally avoid hepatic first pass, but the swallowed part of a buccal or sublingual dose does not.
Imipramine undergoes substantial first-pass loss.
Drugs that are barely metabolised and are excreted unchanged by the kidney, such as sulpiride, amisulpride, pregabalin and lithium, lose almost none of an oral dose to first pass.
Bioequivalence compares the rate and extent of absorption of two formulations of one drug at the same dose by the same route, and decides whether brands are interchangeable.
Distribution
Distribution into tissues is not uniform. It depends on lipid solubility, ionisation, plasma protein binding, capillary permeability and tissue affinity.
Lipid-soluble drugs pass into extracellular and intracellular compartments, whereas large or tightly protein-bound drugs stay mainly in the vascular compartment.
Highly perfused organs equilibrate before muscle and fat.
Only unbound drug crosses membranes, binds receptors and is filtered by the glomerulus.
Albumin mainly binds acidic and neutral drugs, whereas alpha-1 acid glycoprotein binds many basic drugs.
Caffeine reaches saliva at a concentration close to its plasma concentration, because it is lipid soluble and little protein bound.
Weak bases accumulate by ion trapping in relatively acidic compartments, including breast milk.
Volume of distribution
Apparent volume of distribution (Vd) = amount of drug in the body / plasma concentration. It is an apparent volume, not an anatomical one.
A drug confined to plasma has a Vd near 3 litres, and total body water is about 42 litres.
Lithium has a Vd of about 0.7 to 0.9 L/kg, and fluoxetine has a Vd of about 20 to 40 L/kg.
A large Vd limits removal by dialysis, so lithium is dialysable but amitriptyline generally is not.
Metabolism
The liver is the main site of metabolism, and the gut, kidney and blood also contribute.
The lungs are a minor but recognised site of metabolism, unlike the spleen.
Phase | Reactions | Product |
|---|---|---|
I, functionalisation | Oxidation (including hydroxylation and dealkylation), reduction, hydrolysis; often CYP enzymes | A polar group is added or exposed, so the product is more polar and water soluble; activity may rise, fall or become toxic |
II, conjugation | Glucuronidation, sulphation, acetylation, glutathione or amino acid conjugation | Usually excreted more easily, but not always inactive |
Phase II can happen without a phase I step.
Prodrugs
A prodrug is inactive or weakly active until the body metabolises it into the active drug.
An active metabolite that is marketed as a drug, such as paliperidone, is not a prodrug.
An enzyme inducer that speeds a prodrug's activating step raises exposure to the active metabolite and strengthens its effect, which is the reverse of the usual effect of induction.
Lisdexamfetamine is converted in red cells, so CYP induction does not activate it.
Benzodiazepines
The 3-hydroxy benzodiazepines (lorazepam, oxazepam, temazepam) are conjugated directly to glucuronide, with no phase I step and no clinically important active metabolite.
Glucuronidation holds up better than CYP oxidation in cirrhosis, so these drugs are often preferred in liver impairment, although caution is still needed.
Chlordiazepoxide is oxidised by CYP3A4 to desmethylchlordiazepoxide, demoxepam and desmethyldiazepam, all of which are active.
Desmethyldiazepam is also formed from diazepam, and its half-life can exceed 100 hours.
Oxazepam is the common active end-product of diazepam, chlordiazepoxide, clorazepate and temazepam.
Active metabolites of antidepressants and antipsychotics
Tricyclic antidepressants are N-demethylated to active secondary amines. Fluoxetine and sertraline are also N-demethylated to active metabolites.
Parent | Active metabolite | Note |
|---|---|---|
Amitriptyline | Nortriptyline | Licensed separately; less sedating |
Imipramine | Desipramine | Formed in the liver mainly by CYP2C19; marketed separately; more noradrenergic |
Clomipramine | Desmethylclomipramine | |
Trimipramine | Desmethyltrimipramine | |
Dosulepin | Northiaden | |
Fluoxetine | Norfluoxetine | About as potent as the parent |
Sertraline | N-desmethylsertraline | Active; long half-life |
Risperidone | 9-hydroxyrisperidone (paliperidone) | Roughly equipotent; licensed in its own right |
Fluoxetine lasts several days, but norfluoxetine has a half-life of one to two weeks. Clearing both takes about five weeks, which is the long washout needed before a monoamine oxidase inhibitor.
Other selective serotonin reuptake inhibitors have weak or inactive metabolites.
Risperidone has a half-life of about 3 hours in extensive metabolisers. Its 9-hydroxy metabolite lasts about 21 hours, so the active moiety's half-life is near 20 hours.
Factors that change metabolism
Tobacco smoke induces CYP1A2 and lowers tricyclic plasma levels by 25 to 50% in smokers.
Adolescents metabolise tricyclics more extensively than adults, so they clear them faster and need higher weight-adjusted doses.
Elimination
Elimination removes active drug by metabolism or excretion.
Clearance is the volume of plasma cleared of drug per unit time: clearance = rate of elimination / plasma concentration.
Clearance is constant under first-order kinetics, and organ impairment can reduce it.
Tubular secretion can be saturated, and drugs can compete for it.
Lipid-soluble, un-ionised drug is reabsorbed from the tubule more readily.
Ion trapping works in the tubule: acidic urine ionises weak bases such as memantine, which stops their reabsorption and raises their renal elimination.
Urine pH alters amphetamine excretion, but deliberately acidifying the urine is not routine overdose treatment.
Enterohepatic recirculation can prolong exposure.
Renal or hepatic clearance
Gabapentin, pregabalin, lithium, sulpiride and amisulpride escape hepatic metabolism and the kidney clears them unchanged. Pregabalin dosing therefore follows renal function, not hepatic function.
Quetiapine and fluoxetine depend on hepatic metabolism for clearance.
Lithium
Lithium is an ion that is not metabolised, so it has no active metabolite.
About 95% of a dose is excreted unchanged in urine. The kidney filters lithium and reabsorbs most of the filtered amount in the proximal tubule.
Its narrow therapeutic index means toxicity appears at levels only modestly above the target range.
Half-life, steady state and dosing
First-order elimination removes a constant fraction of drug per unit time.
Half-life = 0.693 x Vd / clearance, so a long half-life may reflect slow clearance, wide distribution or both.
With repeated dosing, drug accumulates until input equals elimination. After 1, 2, 3, 4 and 5 half-lives, levels reach 50, 75, 87.5, 94 and 97% of steady state.
Washout time depends on both the half-life and any active metabolites.
Phenytoin and alcohol have saturable kinetics, which need more detailed models.
Loading dose = target concentration x Vd / F.
Maintenance dose rate = target average concentration x clearance / F, so halving clearance halves the dose rate under linear kinetics.
Longer dosing intervals give larger swings between peak and trough levels, which is a hazard with narrow therapeutic index drugs.