DEXTROMETHORPHAN IN NONKETOTIC HYPERGLYCINEMIA - METABOLIC VARIATION CONFOUNDS THE DOSE-RESPONSE RELATIONSHIP

Nonketotic hyperglycinaemia (NKH) is an inborn error of the glycine cl eavage system resulting in seizures and mental retardation. Two prior reports noted an anticonvulsant effect from high-dose dextromethorphan (DM) in this disorder, although the two reported patients demonstrate d widely disparate DM requirements and drug levels. We report two chil dren with NKH who also demonstrated disparate and variable DM metaboli sm which markedly influenced the dose-concentration-response relations hip. Levels of DM and its primary metabolite dextrorphan (DX) were uti lized to guide DM therapy and exhibited patterns reflective of the ext ensive and poor metabolizer phenotypes for CYP2D6, the cytochrome P450 isoform responsible for DM metabolism. In the patient who appeared to represent the extensive metabolizer (EM) phenotype, treatment with th e non-specific cytochrome P450 inhibitor cimetidine was required to re duce biotransformation of DM to DX and, thus, to increase DM plasma co ncentrations, In the patient with the apparent poor metabolizer (PM) p henotype, a change in the DM preparation to a sustained-release form a nd increase in the dosing interval was required to lower DM plasma con centrations. These cases demonstrate the importance of CYP2D6 phenotyp e in providing safe and effective DM therapy to patients with NKH.