title: A cytochrome P450 phenotyping cocktail causing unexpected adverse reactions in female volunteers.
abstract: BACKGROUND
  A four-drug cytochrome P450 (CYP) phenotyping cocktail was developed to rapidly and safely determine CYP2D6, CYP2C19, CYP2C9 and CYP1A2 enzyme activity and phenotype.
  
  
  METHODS
  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.
  
  
  RESULTS
  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].
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, J.B. Winslowsvej 19, 5000, Odense, Denmark, rpedersen@health.sdu.dk.
authors.forename: Rasmus Steen
authors.initials: RS
authors.lastname: Pedersen
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
authors.forename: Mette Marie Hougaard
authors.initials: MM
authors.lastname: Christensen
authors.forename: Kim
authors.initials: K
authors.lastname: Brosen
mesh_terms: D000328:Adult; D002110:Caffeine / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004338:Drug Combinations; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D019808:Losartan / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000009:adverse effects* / Q000493:pharmacokinetics; D010641:Phenotype; D014147:Tramadol / Q000009:adverse effects* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D014147:Tramadol; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D019808:Losartan; D009853:Omeprazole
references.citation: Eur J Clin Pharmacol. 2004 Jul;60(5):337-42
references.pmid: 15197523
references.citation: Eur J Clin Pharmacol. 2009 Sep;65(9):887-94
references.pmid: 19404631
references.citation: Pharmacogenetics. 2002 Aug;12(6):473-8
references.pmid: 12172216
references.citation: Pharmacogenetics. 1995 Dec;5(6):358-63
references.pmid: 8747407
references.citation: Clin Pharmacol Ther. 2003 Jun;73(6):517-28
references.pmid: 12811361
references.citation: Ther Drug Monit. 1996 Jun;18(3):254-62
references.pmid: 8738764
references.citation: Clin Pharmacol Ther. 2005 Jun;77(6):458-67
references.pmid: 15961977
references.citation: Xenobiotica. 2002 May;32(5):411-25
references.pmid: 12065063
references.citation: Br J Clin Pharmacol. 1997 Mar;43(3):253-8
references.pmid: 9088579
references.citation: Pharmacogenetics. 1996 Apr;6(2):159-76
references.pmid: 9156694
references.citation: Clin Pharmacol Ther. 2007 Feb;81(2):270-83
references.pmid: 17259951
references.citation: Clin Pharmacol Ther. 2000 Aug;68(2):199-209
references.pmid: 10976551
references.citation: Clin Pharmacol Ther. 2007 Nov;82(5):531-40
references.pmid: 17392720
references.citation: Basic Clin Pharmacol Toxicol. 2009 Apr;104(4):335-44
references.pmid: 19281600
references.citation: Psychopharmacology (Berl). 2012 Oct;223(4):427-38
references.pmid: 22623016
references.citation: J Pharmacol Exp Ther. 1992 Jan;260(1):275-85
references.pmid: 1309873
references.citation: Clin Pharmacokinet. 2004;43(13):879-923
references.pmid: 15509185
references.citation: Expert Opin Pharmacother. 2012 Jul;13(10):1437-49
references.pmid: 22698264