title: Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes.
abstract: OBJECTIVE
  To determine whether the probe drugs caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin can be simultaneously administered as a metabolic cocktail to estimate in vivo cytochrome P450 (CYP) and N-acetyltransferase enzyme activities.
  
  
  METHODS
  Fourteen healthy nonsmoking male volunteers (mean age +/- SD, 21.6 +/- 2.2 years) received 100 mg caffeine, 250 mg chlorzoxazone, 100 mg dapsone, 10 mg debrisoquin, and 100 mg mephenytoin individually and in four and five-drug combinations in a randomized manner using a 7 x 7 Latin square. Each drug or drug combination was given orally after an overnight fast, with a minimum 1-week washout between administrations. In each session, urine was collected from 0 to 8 hours and plasma was obtained at 4 and 8 hours after drug administration. Plasma and metabolite concentrations were used to estimate phenotypic trait measures for the efficiency of each drug's metabolism.
  
  
  RESULTS
  The phenotypic indexes determined for caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin were not significantly different when given alone than when given in combination. The median percentage change of the trait measures observed during administration of all five compounds compared with individual administration ranged from -10.7% for the 6-hydroxychlorzoxazone to chlorzoxazone plasma ratio to +2.2% for the debrisoquin recovery ratio.
  
  
  CONCLUSIONS
  The results of this study show that caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin in low doses can be simultaneously administered without metabolic interaction. This cocktail approach can thus simultaneously provide independent in vivo phenotypic measures for multiple CYP enzymes and N-acetyltransferase.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, PA 15261, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Frye
authors.forename: G R
authors.initials: GR
authors.lastname: Matzke
authors.forename: A
authors.initials: A
authors.lastname: Adedoyin
authors.forename: J A
authors.initials: JA
authors.lastname: Porter
authors.forename: R A
authors.initials: RA
authors.lastname: Branch
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001191:Arylamine N-Acetyltransferase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002110:Caffeine; D002753:Chlorzoxazone; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D003622:Dapsone; D003647:Debrisoquin; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008617:Mephenytoin; D010641:Phenotype; D012016:Reference Values
chemical_list: D002110:Caffeine; D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D001191:Arylamine N-Acetyltransferase; D002753:Chlorzoxazone; D008617:Mephenytoin; D003647:Debrisoquin