Anaes · Applied cardiovascular & respiratory physiology
Plasma protein binding and drug interactions
Also known as Plasma protein binding · Protein binding · Free fraction · Drug displacement · Drug-drug interaction · Enzyme induction and inhibition
Most drugs circulate partly bound to plasma proteins and partly free, and only the free (unbound) fraction is pharmacologically active, available for distribution, metabolism and excretion. The bound fraction is a reservoir that buffers the free concentration. Understanding plasma protein binding and drug-drug interactions is essential for safe perioperative prescribing. Albumin/AAG preferences, albumin/AAG concentrations, fu arithmetic and displacement/hypoalbuminaemia teaching below are standard textbook framework carried with explicit honesty notes; the retrieved abstracts own only the narrowed points cited inline. Built on the PPB-methods comparison across 26 small molecules with ED/UF/UC concordance R2 0.95 and ED-literature R2 0.97 plus peptide/degrader adaptations and decision tree (Enlo-Scott 2026), the biomimetic-binding-to-Vd review linking IAM phospholipid affinity to distribution with PPB affecting both distribution and clearance (Valko 2026), the IQ Consortium reversible-inhibition assay survey across 25 industry responses with Ki equals IC50/2 and over/underprediction cases (Sensenhauser 2026), the antiseizure CYP2C9/P-gp induction NMA with carbamazepine 600 mg/day strongest CYP2C9 inducer and 300/600 mg/day strongest P-gp inducer (Cohen 2026), the PXR-AOX1 cell/mouse study with rifampicin 5.2-fold AOX1 and 9.5-fold CYP3A4 induction and Pearson 0.83 (Chen 2026), the n-11 grapefruit-juice repeated-intake study inhibiting CYP2B6/2C9/2C19/3A4 with metabolite ratios 0.57/0.78/0.43/0.72 (Aurinsalo 2026), the serotonin-syndrome multisource pharmacovigilance study with linezolid/fentanyl/methylene-blue signals and 10.16 percent not indexed (Xu 2026), and the postoperative serotonin syndrome case after venlafaxine/opioids/stimulants/cannabis with Hunter criteria and supportive reversal (Aboe Aboe 2026).
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- Only the FREE (unbound) drug is active, crosses membranes, is metabolised and excreted. The protein-bound drug is an inert reservoir. For highly bound drugs (warfarin, phenytoin, thyroxine, diazepam — more than 90 percent bound), a small fall in binding produces a large rise in free concentration, so displacement or hypoalbuminaemia can precipitate toxicity.
- Albumin binds ACIDIC drugs; alpha-1-acid glycoprotein binds BASIC drugs (local anaesthetics, opioids, propranolol). Alpha-1-acid glycoprotein is an acute-phase reactant that RISES in inflammation and postoperatively, so the free fraction of basic drugs FALLS after surgery or trauma.
- Enzyme INHIBITION has a rapid onset (hours to days) and raises the affected drug's concentration — classic perpetrators: ketoconazole, erythromycin, clarithromycin, fluoxetine, amiodarone, grapefruit juice (intestinal CYP3A4). Enzyme INDUCTION has a slow onset and offset (weeks) and lowers the affected drug's concentration — classic perpetrators: rifampicin, phenytoin, carbamazepine, barbiturates, chronic alcohol, St John's wort, via the pregnane X receptor.
- Drug interactions are classified as pharmaceutical (infusion incompatibility), pharmacokinetic (altered ADME — displacement or CYP induction/inhibition) and pharmacodynamic (additive/synergistic/antagonistic at a receptor or pathway, e.g. two sedatives, or serotonin syndrome).
- Serotonin syndrome is the most dangerous perioperative pharmacodynamic interaction: combining a serotonergic agent (SSRI, tramadol, pethidine, MAOI, linezolid) with another raises central serotonin, producing agitation, hyperreflexia, clonus, hyperthermia and death. Avoid pethidine and tramadol in patients on SSRIs or MAOIs.
Meet the patient
A 68-year-old woman on long-term warfarin for atrial fibrillation is admitted with a chest infection and started on clarithromycin. Five days later her INR is 9.0 and she has haematuria. The registrar blames protein-binding displacement of warfarin by the macrolide — a tidy, textbook-sounding answer that is mostly wrong.[1]
The real question this topic answers is: when a highly bound drug misbehaves, is it binding, or is it clearance? Almost always it is clearance — CYP inhibition — and blaming displacement sends you after the wrong fix. Hold that question and the whole of protein-binding pharmacology falls into place.[1]
References8ShowHide
- [1]Enlo-Scott Z, et al. A framework for plasma protein binding: Comparing methods for diverse small molecules and adapting for novel modalities J Pharm Sci, 2026.PMID 42309206
- [2]Valko K Linking biomimetic binding measurements to pharmacokinetic models of volume of distribution and hepatic clearance ADMET DMPK, 2026.PMID 42100636
- [3]Sensenhauser C, et al. In vitro reversible enzyme inhibition assays to predict drug-drug interactions: Current state and industry perspective from the IQ Consortium Enzyme Inhibition Working Group Drug Metab Dispos, 2026.PMID 42275929
- [4]Cohen H, et al. Induction of cytochrome P450 2C9 and P-glycoprotein activity by antiseizure medications: A systematic review and network meta-analysis Epileptic Disord, 2026.PMID 41948839
- [5]Chen S, et al. Role of pregnane X receptor in the upregulation of human aldehyde oxidase gene expression Biochem Pharmacol, 2026.PMID 42178049
- [6]Aurinsalo L, et al. Repeated Intake of Grapefruit Juice Inhibits CYP2B6, CYP2C9, CYP2C19, and CYP3A4 while Lingonberry Powder Does Not Induce Major CYP Enzymes in Humans Clin Pharmacol Ther, 2026.PMID 41390976
- [7]Xu S, et al. Detection of clinically significant drug-drug interactions in serotonin syndrome: a multisource real-world data and pharmacovigilance study Ther Adv Drug Saf, 2026.PMID 42317468
- [8]Aboe Aboe MN, Wege N [Postoperative serotonin syndrome in a patient with attention-deficit/hyperactivity disorder and treatment-resistant depression]. Praxis (Bern 1994), 2026.PMID 42346977