Dextromethorphan in nonketotic hyperglycinaemia: metabolic variation confounds the dose-response relationship.
Nonketotic hyperglycinaemia (NKH) is an inborn error of the glycine cleavage 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 demonstrated widely disparate DM requirements and drug levels. We report two children with NKH who also demonstrated disparate and variable DM metabolism which markedly influenced the dose-concentration-response relationship. Levels of DM and its primary metabolite dextrorphan (DX) were utilized to guide DM therapy and exhibited patterns reflective of the extensive 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 the non-specific cytochrome P450 inhibitor cimetidine was required to reduce biotransformation of DM to DX and, thus, to increase DM plasma concentrations. In the patient with the apparent poor metabolizer (PM) phenotype, a change in the DM preparation to a sustained-release form and increase in the dosing interval was required to lower DM plasma concentrations. These cases demonstrate the importance of CYP2D6 phenotype in providing safe and effective DM therapy to patients with NKH.
Arnold
G L
GL
Department of Pediatrics, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Griebel
M L
ML
Valentine
J L
JL
Koroma
D M
DM
Kearns
G L
GL
D002648:Child; D003915:Dextromethorphan / Q000378:metabolism* / Q000627:therapeutic use; D003917:Dextrorphan / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006944:Hyperglycemic Hyperosmolar Nonketotic Coma / Q000188:drug therapy / Q000378:metabolism*; D007231:Infant, Newborn; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D012640:Seizures
D003917:Dextrorphan; D016202:N-Methylaspartate; D003915:Dextromethorphan