Enzymes, transporters and receptors that medicines modulate — what they are, what they do and how they explain interactions.
BCRP inhibition increases exposure to substrates such as rosuvastatin, methotrexate and sulfasalazine; combination with inhibitors (e.g. ciclosporin) may require dose reduction.
COX-1 inhibition by NSAIDs and aspirin explains the gastrotoxic effects (ulcer, bleeding) and, with aspirin, the antiplatelet effect. It is the target of NSAID + anticoagulant/antiplatelet interactions.
Selective COX-2 inhibitors spare COX-1 and have lower gastrointestinal risk, but retain cardiovascular (thromboembolic) and renal risk; interactions with anticoagulants remain relevant.
CYP1A2 inhibition (e.g. ciprofloxacin + theophylline) increases the risk of theophylline toxicity (nausea, tachycardia, seizures); smokers who quit may accumulate substrates metabolised by this enzyme.
CYP2B6 induction (e.g. rifampicin, phenobarbital) lowers efavirenz and bupropion concentrations; inhibition increases exposure.
CYP2C19 inhibition (e.g. omeprazole + clopidogrel) reduces formation of the active clopidogrel metabolite and may decrease antiplatelet protection; induction (rifampicin) accelerates substrate metabolism.
CYP2C8 inhibition (e.g. gemfibrozil + repaglinide) raises substrate concentrations and the risk of hypoglycaemia; induction reduces the effect.
CYP2C9 inhibition (e.g. fluconazole, amiodarone, metronidazole, cotrimoxazole) is the central mechanism of interactions that raise INR with coumarins; induction (rifampicin) reduces the anticoagulant effect.
CYP2D6 inhibition (e.g. fluoxetine, paroxetine) can double concentrations of substrates such as codeine, tramadol and metoprolol; in poor metabolisers, prodrugs activated by this enzyme (codeine → morphine) may have reduced effect.
Chronic alcohol intake induces CYP2E1 and increases NAPQI formation from paracetamol, raising the risk of hepatotoxicity at therapeutic doses.
It is the most frequent target in interactions: drugs that inhibit it (e.g. ketoconazole, clarithromycin, grapefruit juice) raise substrate concentrations; drugs that induce it (e.g. rifampicin, carbamazepine, phenytoin) lower them and may cause loss of efficacy.
DAT inhibition raises synaptic dopamine; drugs that inhibit DAT (methylphenidate, bupropion) can interact with other dopaminergic agents.
DPP-4 inhibitors (gliptins) prolong incretin action and increase insulin secretion; should not be combined with insulin or secretagogues without dose adjustment (hypoglycaemia risk).
Oxidant drugs can cause acute haemolysis in G6PD-deficient patients: primaquine, sulfonamides (cotrimoxazole), nitrofurantoin, dapsone, high-dose aspirin.
Many drugs from diverse classes (antipsychotics, macrolide antibiotics, antiarrhythmics, antidepressants) inhibit hERG and prolong QT; co-administration of multiple hERG inhibitors increases risk additively.
Statins (simvastatin, atorvastatin) are metabolised by CYP3A4 and transported by OATP1B1; inhibition by ketoconazole, clarithromycin, ciclosporin or amiodarone increases the risk of myopathy and rhabdomyolysis.
MAO-A inhibition raises synaptic monoamines; combination with SSRIs, tramadol, pethidine or dextromethorphan can cause serotonin syndrome, and tyramine-rich food can cause a hypertensive crisis.
Selective MAO-B inhibition at therapeutic doses has lower tyramine interaction risk, but combination with serotonergic drugs (SSRIs, pethidine) retains serotonin syndrome risk.
NET inhibition raises synaptic norepinephrine; serotonergic drugs that also inhibit NET (venlafaxine, duloxetine) may cause hypertension through noradrenergic potentiation.
OAT1/OAT3 inhibition (e.g. probenecid, NSAIDs, cotrimoxazole) reduces tubular secretion of substrates and raises plasma concentrations; probenecid is intentionally used to prolong penicillin action.
OATP1B1 inhibition (e.g. ciclosporin, clarithromycin) reduces hepatic uptake of statins and raises systemic concentrations, with risk of myopathy and rhabdomyolysis.
OCT2 inhibition (e.g. cimetidine, trimethoprim) reduces tubular secretion of metformine, raising plasma concentrations and the risk of adverse effects (lactic acidosis). Ranitidine is both a substrate and a weak OCT2 inhibitor.
Drugs that inhibit P-gp (e.g. amiodarone, clarithromycin, ketoconazole, verapamil, diltiazem) increase absorption and concentrations of substrates such as digoxin, dabigatran and tacrolimus; inducers lower them.
Combining PDE5 inhibitors with nitrates (nitroglycerin, isosorbide) causes severe, potentially fatal hypotension, by potentiating nitric oxide; they also potentiate hypotension with alpha-blockers and riociguat.
Drugs that activate PPAR-γ (thiazolidinediones) improve insulin sensitivity but may cause fluid retention, heart failure and fractures; combination with insulin or sulfonylureas increases hypoglycaemia risk.
Drugs that activate PXR (e.g. rifampicin, carbamazepine, phenytoin) increase transcription of CYP3A4 and other targets, lowering concentrations of multiple substrates — the mechanism behind rifampicin's multiple drug interactions.
SERT inhibition raises synaptic serotonin; combining multiple serotonergic drugs (SSRI + tramadol, SSRI + MAOI, SSRI + linezolid) can cause serotonin syndrome.
Drugs that inhibit TPMT (e.g. allopurinol) increase azathioprine toxicity; allopurinol + azathioprine is the classic interaction and requires azathioprine dose reduction.
UGT1A1 inhibition (e.g. valproate, fluconazole) may increase toxicity of drugs metabolised by glucuronidation; genetic deficiency (Gilbert syndrome) affects irinotecan and bilirubin elimination.
Warfarin and acenocoumarol inhibit VKORC1, reducing synthesis of vitamin K-dependent factors; dietary vitamin K intake antagonises this effect and shifts the INR.
