Table 1.
Cytochrome P450 single nucleotide polymorphisms relevant to methadone metabolism.
| Alleles | dbSNP ID† | Key sequence change‡ | Effect and key amino acid substitution (if any) |
Effect on enzyme activity | Ref. | |
|---|---|---|---|---|---|---|
| CYP1A2*1F | rs762551 | intron 1, c.−9–154C > A | No influence on (R)-, (S)-, or (R,S)-MTD levels at trough or peak | [64] | ||
| CYP2B6*2 | rs8192709 | c.64C > T | R22C | ↑ [(R,S)-MTD]/[EDDP] ratio | [72] | |
| CYP2B6*4 | rs2279343 | c.785A > G | K262R | ↑ (R,S)-MTD plasma levels | [73,74] | |
| ↓ (R,S)-MTD plasma levels | [75,76] | |||||
| ↑ MTD clearance | ||||||
| ↑ (R)- and (S)-MTD N-demethylation | ||||||
| CYP2B6*5 | rs3211371 | c.1459C > T | R487C | ↓ (S)-MTD plasma levels | [32] | |
| ↑ (S)-MTD clearance | ||||||
| No effect on MTD clearance | [75] | |||||
| ↑ (R,S)-MTD plasma levels | [72] | |||||
| CYP2B6*6 | rs2279343 | c.785A > G | K262R | ↑ (S)- and (R,S)-MTD plasma levels | [64,67,75–79] | |
| rs3745274 | c.516G > T | Q172H | ↑ MTD/Dose plasma ratio | |||
| ↓ (R)- and (S)-MTD N-demethylation | ||||||
| ↓ MTD clearance | ||||||
| CYP2B6*9 | rs3745274 | c.516G > T | Q172H | ↑ (R,S)-MTD plasma levels | [74,76,80] | |
| ↑ [(S)-MTD/MTD Dose] plasma ratio | ||||||
| ↓ (R)- and (S)-MTD N-demethylation | ||||||
| ↓ (S)-MTD clearance | ||||||
| CYP2B6*11 | rs35303484 | c.136A > G | M46V | ↑ (S)-MTD plasma levels | [32] | |
| ↓ (S)-MTD clearance | ||||||
| CYP2B6 3′UTR | rs707265 | c.*1355A > G | ↑ [(S)-MTD/MTD Dose] plasma ratio | [80] | ||
| ↓ (S)-MTD clearance | ||||||
| CYP2B6 3′UTR | rslO38376 | 3’UTR, c.*1277A > T | ↑ [(S)-MTD/MTD Dose] plasma ratio | [80] | ||
| ↓ (S)-MTD clearance | ||||||
| CYP2B6 intron 1 | rsl0403955 | c.172–468 T > G | ↑ [(S)-MTD/MTD Dose] plasma ratio | [80] | ||
| ↓ (S)-MTD clearance | ||||||
| CYP2B6 intron 5 | rs2279345 | c.923–197T > C | ↑ [(S)-MTD/MTD Dose] plasma ratio | [80] | ||
| ↓ (S)-MTD clearance | ||||||
| CYP2C9*2 | rsl799853 | c.430C > T | R144C | No effect on MTD plasma levels | [64,77,82] | |
| ↑ MTD/Dose plasma ratio | [78] | |||||
| CYP2C9*3 | rsl057910 | c.1075A > C | I359L | No effect on MTD plasma levels | [64,77,82] | |
| ↑ MTD/Dose plasma ratio | [78] | |||||
| CYP2C19*2 | rs4244285 | c.681G > A | I331V; splicing defect | No effect on MTD plasma levels | [64,77,82] | |
| ↑ (R)-MTD plasma levels | [78,86] | |||||
| ↑ MTD/Dose plasma ratio | ||||||
| ↑ EDDP plasma levels | [87] | |||||
| CYP2C19*3 | rs4986893 | c.636G > A | W212X; stop codon | No effect on MTD plasma levels | [64,77] | |
| ↑ MTD/Dose plasma ratio | [78] | |||||
| CYP3A4*1B | rs2740574 | 5’UTR, C, −392A > G |
↑ (S)-MTD plasma levels | [64] | ||
| CYP3A5*3 | rs776746 | 5’UTR, c.219–237A > G |
Splicing defect | No effect on MTD plasma levels | [64,82] | |
| ↑ MTD metabolism | [94] | |||||
| (*1/*3 carrier) | ||||||
| ↑ MTD/Dose plasma ratio (*3/*3) | [78] |
More comprehensive information is available from the Human Cytochrome P450 Allele Nomenclature Committee [69].
CYP, cytochrome P450; MTD, methadone; EDDP, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine; UTR, untranslated region.
†
National Center for Biotechnology Information (NCBI) dbSNP [88].
‡
Location of sequence change on mRNA for the respective CYP NM accession number [88].