20 - Genetics of cytochrome function

Genetics of cytochrome function

888 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 11 Genetics of cytochrome function The function of CYPs is under genetic control. Each individual’s CYP function is determined by heredity and is often, but not always, linked to ethnicity. Phenotypes are usually described as poor metabolisers, intermediate metabolisers, normal metabolisers and rapid or ultrarapid metabolisers. Table 11.6 gives the approximate distribution of phenotypes across nine ethnicities. Awareness of differences in phenotype frequencies can help predict and understand drug metabolism differences. As an example, CYP1A2 ultrarapid metaboliser phenotypes are most often seen in African Americans and so we might expect a higher rate of clozapine failure (or at least low plasma levels) in this population.

Table 11.6  Estimated phenotype frequency by ancestry for CYP1A2, CYP2D6, CYP2C19, CYP2C9 and CYP3A4.10–22 Genotype-­predicted phenotypes African10,11 African American12,13 European ancestry + North American14 Near Eastern East Asian South/Central Asian Americas Latino15 Oceanian CYP1A2 Ultrarapid metaboliser 10–20% 15–30% 1–4% 5–10% 1–5% 3–8% 5–10% 7–12% 5–10% Normal metaboliser 55–70% 50–60% 70–80% 65–75% 65–75% 60–70% 60–70% 65–75% 65–75% Intermediate metaboliser 10–20% 10–15% 10–15% 10–15% 10–20% 10–15% 10–15% 10–15% 10–15% Poor metaboliser 5–10% 5–10% 5–10% 5–10% 10–15% 10–15% 5–10% 5–10% 5–10% CYP2D6 Ultrarapid metaboliser 4% 5% 3% 10% 1% 2% 6% 4% 20% Normal metaboliser 43% 56% 51% 55% 52% 62% 64% 59% 67% Intermediate metaboliser 44% 36% 39% 30% 39% 30% 24% 29% 10% Poor metaboliser 2% 2% 7% 2% 1% 2% 2% 3% 0% CYP2C19 Ultrarapid metaboliser 3% 4% 5% 4% 0% 3% 1% 3% 0% Rapid metaboliser 19% 24% 27% 26% 3% 19% 14% 24% 2% Normal metaboliser 30% 33% 40% 45% 38% 30% 63% 53% 4% Intermediate metaboliser 36% 31% 26% 24% 46% 41% 21% 19% 37% Likely intermediate metaboliser 4% 3% 0% 0% 0% 0% 0% 0% 0% Poor metaboliser 6% 4% 2% 2% 13% 8% 2% 1% 57% Likely poor metaboliser 1% 1% 0% 0% 0% 0% 0% 0% 0% CYP2C9 Normal metaboliser 73% 76% 63% 61% 84% 60% 83% 75% 91% (Continued )

Table 11.6  (Continued ) Genotype-­predicted phenotypes African10,11 African American12,13 European ancestry + North American14 Near Eastern East Asian South/Central Asian Americas Latino15 Oceanian Intermediate metaboliser 26% 24% 35% 36% 15% 36% 16% 25% 9% Poor metaboliser 1% 1% 3% 3% 1% 4% 0% 1% 0% CYP3A4 Ultrarapid metaboliser 7–15% 10–15% 1–5% 5–10% 1–4% 2–6% 4–9% 3–8% 4–10% Normal metaboliser 50–65% 55–70% 65–75% 60–70% 60–75% 60–70% 55–65% 60–70% 60–70% Intermediate metaboliser 15–25% 10–20% 15–20% 15–20% 15–25% 15–20% 15–20% 15–20% 15–20% Poor metaboliser 5–10% 5–10% 5–10% 5–10% 5–10% 5–10% 5–10% 5–10% 5–10%