The Karolinska cocktail for phenotyping of five human cytochrome P450 enzymes

被引:130
作者
Christensen, M [1 ]
Andersson, K
Dalén, P
Mirghani, RA
Muirhead, GJ
Nordmark, A
Tybring, G
Wahlberg, A
Yasar, Ü
Bertilsson, L
机构
[1] Huddinge Univ Hosp, Div Clin Pharmacol, Karolinska Inst, Dept Lab Med, S-14186 Stockholm, Sweden
[2] Pfizer Ltd, Clin Sci, Clin Pharmacokinet Pharmacodynam, Sandwich CT13 9NJ, Kent, England
关键词
D O I
10.1016/S0009-9236(03)00050-X
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Objectives: Our objectives were (1) to determine whether the drugs caffeine, losartan, omeprazole, debrisoquin (INN, debrisoquine), and quinine can be given simultaneously in low doses as a cocktail for the phenotyping of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2136, and 3A4, respectively, and (2) to design an administration schedule to give as few sampling occasions as possible. Methods: Twenty-four subjects were given oral doses of 100 mg caffeine, 25 mg losartan, 20 mg omeprazole, 10 mg debrisoquin, and 250 mg quinine on separate days. After a washout period of at least 4 days, all drugs were given simultaneously except for quinine, which was given 8 hours after the other drugs. Blood and urine samples were collected to determine parent drug and metabolite concentrations for assessment of phenotyping indices. Amy difference between both single and cocktail doses was tested on a log-normal distribution. Results: The phenotypic indices of CYP1A2 (paraxanthine/caffeine in 4-hour plasma), CYP2C9 (losartan/E-3174 [metabolite of losartan] in 0- to 8-hour urine), CYP2C19 (omeprazole/5-hydroxyomeprazole in 3-hour plasma), and CYP3A4 (quinine/3-hydroxyquinine in 16-hour plasma) were not significantly changed when probe drugs were administered alone compared with together, although a tendency toward higher concentrations of losartan was seen during simultaneous administration (95% confidence interval, 0.51-1.002; P = .051). The CYP2D6 phenotypic index (debrisoquin/4-hydroxydebrisoquin in 0- to 8-hour urine) was significantly changed when drugs were given together (95% confidence interval, 0.45-0.87; P = .007), indicating an inhibition of the debrisoquin metabolism. The within-subject coefficients of variation (8%-25%) were much lower than the between-subject coefficients of variation (34%-79%). Conclusions. The administration of drugs together suggests an inhibition of debrisoquin metabolism caused by the concurrent drugs given. By separating debrisoquin from the other cocktail drugs, this method is likely to be used as a toot to phenotype the enzymes CYPIA2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 with only 2 urinary collections and 2 blood-sampling occasions.
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页码:517 / 528
页数:12
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共 41 条
  • [1] INTERACTION BETWEEN 2 PROBES USED FOR PHENOTYPING CYTOCHROMES P4501A2 (CAFFEINE) AND P4502E1 (CHLORZOXAZONE) IN HUMANS
    BERTHOU, F
    GOASDUFF, T
    LUCAS, D
    DREANO, Y
    LEBOT, MH
    MENEZ, JF
    [J]. PHARMACOGENETICS, 1995, 5 (02): : 72 - 79
  • [2] PRONOUNCED DIFFERENCES BETWEEN NATIVE CHINESE AND SWEDISH POPULATIONS IN THE POLYMORPHIC HYDROXYLATIONS OF DEBRISOQUIN AND S-MEPHENYTOIN
    BERTILSSON, L
    LOU, YQ
    DU, YL
    LIU, Y
    KUANG, TY
    LIAO, XM
    WANG, KY
    REVIRIEGO, J
    ISELIUS, L
    SJOQVIST, F
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 1992, 51 (04) : 388 - 397
  • [3] A COCKTAIL STRATEGY TO ASSESS INVIVO OXIDATIVE DRUG-METABOLISM IN HUMANS
    BREIMER, DD
    SCHELLENS, JHM
    [J]. TRENDS IN PHARMACOLOGICAL SCIENCES, 1990, 11 (06) : 223 - 225
  • [4] Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine
    Carrillo, JA
    Christensen, M
    Ramos, SI
    Alm, C
    Dahl, ML
    Benítez, J
    Bertilsson, L
    [J]. THERAPEUTIC DRUG MONITORING, 2000, 22 (04) : 409 - 417
  • [5] Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: Comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype
    Chang, M
    Dahl, ML
    Tybring, G
    Gotharson, E
    Bertilsson, L
    [J]. PHARMACOGENETICS, 1995, 5 (06): : 358 - 363
  • [6] ANALYSIS OF THE CYP2D6 GENE IN RELATION TO DEBRISOQUIN AND DESIPRAMINE HYDROXYLATION IN A SWEDISH POPULATION
    DAHL, ML
    JOHANSSON, I
    PALMERTZ, MP
    INGELMANSUNDBERG, M
    SJOQVIST, F
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 1992, 51 (01) : 12 - 17
  • [7] Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians
    Droll, K
    Bruce-Mensah, K
    Otton, SV
    Gaedigk, A
    Sellers, EM
    Tyndale, RF
    [J]. PHARMACOGENETICS, 1998, 8 (04): : 325 - 333
  • [8] Quinoline antimalarials: Mechanisms of action and resistance and prospects for new agents
    Foley, M
    Tilley, L
    [J]. PHARMACOLOGY & THERAPEUTICS, 1998, 79 (01) : 55 - 87
  • [9] Validation of the five-drug ''Pittsburgh cocktail'' approach for assessment of selective regulation of drug-metabolizing enzymes
    Frye, RF
    Matzke, GR
    Adedoyin, A
    Porter, JA
    Branch, RA
    [J]. CLINICAL PHARMACOLOGY & THERAPEUTICS, 1997, 62 (04) : 365 - 376
  • [10] Evaluation of caffeine as a test drug for CYPIA2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations
    Fuhr, U
    Rost, KL
    Engelhardt, R
    Sachs, M
    Liermann, D
    Belloc, C
    Beaune, P
    Janezic, S
    Grant, D
    Meyer, UA
    Staib, AH
    [J]. PHARMACOGENETICS, 1996, 6 (02): : 159 - 176