PharmacologyTier 1Medical Sciences concept

Renal tubular drug secretion (organic cation/anion transporters)

Core concept

The proximal tubule secretes drugs actively - a mechanism separate from filtration, capable of clearing protein-bound drug that filtration cannot
Two parallel systems, each a basolateral uptake step then an apical efflux step

System	Basolateral uptake	Apical efflux	Substrates
Organic anion (OAT)	OAT1, OAT3	MRP2/4, BCRP	Acids - penicillins, cephalosporins, methotrexate, frusemide, thiazides, NSAIDs, probenecid, urate, aciclovir, ciprofloxacin
Organic cation (OCT)	OCT2	MATE1, MATE2-K	Bases - metformin, creatinine, trimethoprim, cimetidine, dofetilide, procainamide, ranitidine
P-glycoprotein	-	Apical efflux	Digoxin, DOACs, ciclosporin

Competition at a shared transporter -> the drug excreted less efficiently accumulates
Loop and thiazide diuretics only work from the luminal side - they must be secreted by OAT to reach their target, which is why they fail in advanced CKD and compete with uraemic anions and NSAIDs

Trimethoprim raises creatinine without reducing GFR
- Competes with creatinine at OCT2/MATE -> dec tubular creatinine secretion
- Creatinine rises 10-30%; urea, cystatin C and true GFR are unchanged
- Reversible on stopping - not nephrotoxicity
- Same phenomenon: cimetidine, cobicistat, dolutegravir, ritonavir, pyrimethamine
- Trimethoprim also causes true hyperkalaemia by blocking ENaC (an amiloride-like effect) - so the creatinine is fake, the potassium is real
Probenecid blocks OAT-mediated secretion -> prolongs penicillin levels (its original use) and raises methotrexate dangerously; it also blocks urate reabsorption at URAT1
NSAIDs, penicillins and probenecid reduce methotrexate clearance -> a well-recognised cause of severe methotrexate toxicity
Metformin and cimetidine/dolutegravir compete at OCT2 -> inc metformin exposure
Digoxin and P-gp inhibitors (verapamil, amiodarone, clarithromycin) -> dec renal secretion -> inc digoxin
Cystatin C-based eGFR is the workaround where creatinine secretion is blocked or muscle mass is atypical

A modest creatinine rise after starting trimethoprim (or cotrimoxazole) is expected - check the potassium, but do not diagnose AKI on the creatinine alone; consider cystatin C if it matters
Do not co-prescribe NSAIDs, penicillins or probenecid with methotrexate, including with low-dose weekly methotrexate for rheumatoid arthritis
Recognise the pattern: a "renal failure" that resolves within days of stopping a drug and never changed the urea
Diuretic resistance in CKD is partly transport competition - higher loop diuretic doses are needed to deliver enough drug to the lumen
Renal drug secretion is saturable and declines with age - contributing to the accumulation of renally secreted drugs in the elderly

Renal tubule segment function; renal clearance physiology (PAH as the OAT substrate)
P-glycoprotein-mediated drug interactions
Diuretic classes - site and mechanism
Crystal nephropathy - methotrexate
Uricosuric drugs - URAT1

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