Duplication of CYP2D6 predicts high clearance of desipramine but high clearance does not predict duplication of CYP2D6

Objective: Duplication of CYP2D6 causes very rapid metabolism of CYP2D6 substrates such as desipramine. However, we have previously shown that in the Danish population, only about 15% of very rapid metabolisers, defined as subjects with a metabolic ratio of sparteine of 0.15 or less, carried a duplicated allele. The question is whether gene duplication is a relatively rare cause (perhaps predictor) of very rapid metabolism or whether a low metabolic ratio is a poor predictor of this. Methods: After measuring metabolic ratios anew, we selected six volunteers with duplication of CYP2D6 and metabolic ratios ranging from 0.07 to 0.17 and six volunteers without duplication with metabolic ratios ranging from 0.08 to 0.21. Each subject took 100 mg of desipramine. Blood and urine were collected for 48 h. Results: The median total oral clearance of desipramine was 372 1/h and 196 1/h [median difference 1081/h (95.9% c.i., -304-598 1/h)] and the median partial clearance of desipramine by 2-hydroxylation was 155 1/h and 87 1/h [median difference 47 1/h (95.9% c.i., -124-141 1/h)] for the group with duplication and the group without duplication, respectively. Conclusion: The predictive value of duplication of CYP2D6 is poor; there must be other causes (or predictors) of very rapid metabolism and with much higher frequency than duplication of CYP2D6.