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Dextromethorphan in nonketotic hyperglycinaemia: metabolic variation confounds the dose‐response relationship
Author(s) -
Arnold G. L.,
Griebel M. L.,
Valentine J. L.,
Koroma D. M.,
Kearns G. L.
Publication year - 1997
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1023/a:1005301321635
Subject(s) - dextromethorphan , dextrorphan , cyp2d6 , pharmacology , metabolite , pharmacogenetics , active metabolite , medicine , endocrinology , pharmacokinetics , cytochrome p450 , debrisoquine , tolbutamide , metabolism , chemistry , genotype , diabetes mellitus , biochemistry , gene
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.