Dextromethorphan

pharmacological · nervous · Oral

Dextromethorphan. OTC antitussive acting centrally on the medullary cough reflex. The parent compound is a sigma-1 receptor agonist and weak… Oral half-life 2.4 h.

OTC antitussive acting centrally on the medullary cough reflex. The parent compound is a sigma-1 receptor agonist and weak NMDA receptor antagonist; the principal active metabolite dextrorphan (formed by CYP2D6 O-demethylation) is a much more potent NMDA antagonist and the source of the dissociative effects seen at supratherapeutic doses. CYP2D6 elimination is so dominant that DXM AUC differs ~150-fold between extensive and poor metabolizers — DXM is the canonical CYP2D6 probe substrate in phenotyping protocols. Secondary metabolism is N-demethylation by CYP3A4 to 3-methoxymorphinan. PK (Capon 1996 PMID:8841152 EM cohort, 30 mg PO single): EM median t½ 2.4 h, PM t½ 19.1 h (150-fold AUC difference between phenotypes — the canonical CYP2D6-polymorphism magnitude). EM F low (~11%) due to extensive first-pass CYP2D6; quinidine bumps EM AUC 43-fold (the DMQ combination product for pseudobulbar affect). Authored at EM phenotype default; phenotype-aware PK would split EM vs PM populations.

PK: Capon 1996 (PMID:8841152), 30 mg single dose, verbatim "2.4 hours in extensive metabolizers" (median; 19.1 h in poor metabolizers). No human abstract states ka, V or F; the formerly stored F 0.11 / V 300 L match the canine values of KuKanich 2004 (PMID:15500572) and were removed as a species misattribution. PK: AN EARLIER PASS DIAGNOSED THIS RECORD CORRECTLY AND THEN MADE IT SEVENTY TIMES WORSE. It found the stored bioavailability and volume to be DOG values and removed them as a species misattribution, which was right — and removing them did not silence the record, it made it assert the solver defaults instead, 0.9 and 35 L, for a drug whose own mechanism text says first-pass metabolism is so extensive that exposure differs a hundred and fifty fold between metaboliser phenotypes. The defaults put the rendered peak roughly a hundred times above reality; THE DOG VALUES, WRONG AS THEY WERE, HAD BEEN WITHIN A FACTOR OF TWO. THE REPLACEMENT COMES FROM THE RECORD OWN CITATION, which states the two numbers that fix it in one sentence each: "The apparent partial clearance of dextromethorphan to dextrorphan was 1.2 L/hr in poor metabolizers, 78.5 L/hr in extensive metabolizers given quinidine, and 970 L/hr in extensive metabolizers" and "2.4 hours in extensive metabolizers". The volume is those two combined and is therefore DERIVED, NOT VERBATIM — and it is a LOWER BOUND, because 970 is the clearance to ONE metabolite while the total must be at least that. For this drug the bound is tight: the route measured is the dominant one in extensive metabolisers. The record is authored at the extensive-metaboliser phenotype throughout, which its own prose already declares.

Pharmacokinetics

Sources: PMID:8841152