A cytochrome P450 phenotyping cocktail causing unexpected adverse reactions in female volunteers

Abstract

A four-drug cytochrome P450 (CYP) phenotyping cocktail was developed to rapidly and safely determine CYP2D6, CYP2C19, CYP2C9 and CYP1A2 enzyme activity and phenotype. The cocktail consisted of the single CYP phenotyping probes of 50 mg tramadol (CYP2D6), 20 mg omeprazole (CYP2C19), 25 mg losartan (CYP2C9) and 200 mg caffeine (CYP1A2) and was administered as a single oral dose. For enzyme activity measurements, urine was collected as 8 h post-administration and blood was sampled at 4 h. The enzyme activity was determined by metabolic ratios of molar concentrations of the drugs and their enzyme catalyzed metabolites and was correlated to the relevant genotypes. In a pilot study in 12 healthy male volunteers the CYP genotype-phenotype correlation and robustness of the cocktail was successfully determined without detection of any adverse drug reactions. In the subsequent population study, four female volunteers experienced unexpected and unacceptable moderate and severe adverse reactions (ARs) of headache, dizziness, nausea, vomiting, blue fingers, nails and lips and difficulties in urinating, which led to the study being prematurely terminated after inclusion of only 22 subjects (15 males, 7 females) [corrected]. Attention must be paid to adverse reactions when designing new combinations of phenotype cocktails regardless of the doses and drugs involved. We specifically warn against the combination of tramadol, omeprazole, losartan and caffeine.