Abstract
The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men. These volunteers participated in three clinical studies and received a single oral dose of 30mg DM-HBr. Data were modeled simultaneously using the population pharmacokinetics NONMEM software. A five-compartment model adequately described the data. The activity levels of the alleles assessed differed significantly. The clearance attributable to an individual CYP2D6*1 copy was 2.5-fold higher as compared with CYP2D6*2 (5,010 vs. 2,020l/h), whereas the metabolic activity of CYP2D6*41 was very low (85l/h). Urinary pH was confirmed as a significant covariate for DM renal clearance. These results refine genotype-based predictions of pharmacokinetics for DM and presumably for other CYP2D6 substrates as well.
Highlights
Dextromethorphan (DM) is an antitussive drug with rapid absorption from the gastrointestinal tract after oral administration and a large central volume of distribution 961 L ranging from 585 to 1292 litres.[1]. DM undergoes rapid and extensive first-pass metabolism mainly by cytochrome P450 2D6 (CYP2D6) with an oral bioavailability ranging from 1% to 2% and about 80% in extensive and poor CYP2D6 metabolizer subjects, respectively[2] Its intrinsic hepatic clearance was about 22L/h and 4737 L/h in respective CYP2D6 metabolizer groupss,.(2) In another study a value of 1280 ± 483 L/h for its apparent clearance has been reported for CYP2D6 extensive metabolizers.[3]. Primary metabolic steps include formation of dextrorphan (DO) mainly by CYP2D6 and of 3-methoxymorphinan by CYP3A enzymes
Because the overall disposition of DM is highly dependent on CYP2D6 activity, these polymorphisms are the main source for the wide interindividual variation in its plasma levels and response.[8, 9] For other CYP2D6 substrates such as antidepressants and antipsychotic drugs such variability can lead to failure of treatment in carriers of alleles encoding very high CYP2D6 activity or may expose individuals carrying alleles conferring no or low activity to a high risk of toxicity.[10, 11] for some opioids such as dihydrocodeine, codeine and tramadol, where a highly active metabolite is formed by CYP2D6, therapeutic failure may be associated with low activity genotypes and toxicity with genotypes resulting in high enzymatic activity.[12, 13]
The results suggest that quantitative differences in DM based phenotyping metrics between CYP2D6 genotypes are similar to the differences in enzyme activity, despite additional processes with impact on DM pharmacokinetics
Summary
Dextromethorphan (DM) is an antitussive drug with rapid absorption from the gastrointestinal tract (ka= 2.6 +/- 0.9 h-1) after oral administration and a large central volume of distribution 961 L ranging from 585 to 1292 litres.[1]. Wide variability in CYP2D6 activity is observed between subjects with different functional genotypes, but is rather the rule than the exception among subjects within a genotype group.[16] Attempts to better classify especially those subjects carrying gene duplications and reduced function alleles, ultra-rapid and intermediate metabolizers subgroups have been introduced creating a polymodal population distribution.[17] Another system called semi-quantitative scoring system defining categories for CYP2D6 alleles has been developed[18] which assigns scores to each allele (1 for fully functional alleles, 0.5 for reduced activity functional alleles, and zero for non-functional alleles) and uses these ‘gene doses’ as an indicator for phenotype. These classification systems have improved phenotype prediction, considerable variability within score groups persists
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