between ritonavir and fluticasone (http://www.fda.gov/cder/foi/label/2004/
20549slr016,20548slr020,20121slr030_flonase_lbl.pdf). In a multiple-dose,
crossover drug interaction study in 18 healthy subjects fluticasone nasal spray
(200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg
twice daily). The fluticasone AUC was elevated by 368-fold after coadminis-
tration of ritonavir with fluticasone nasal spray (Table 7.8). Clinical cases
have been reported for patients with AIDS who suffered from asthma
and developed an iatrogenic Cushing’s syndrome subsequent to receiving
both fluticasone and ritonavir at the same time (Hillebrand-Haverkort et al.,
1999).
7.4.2.3 Cocktail Approaches Simultaneous administration of a mixture of
two or more probe substrates of CYP enzymes in one study in human
volunteers is referred to as a ‘‘cocktail approach.’’
A number of drug metabolism cocktails have been proposed and evaluated
in clinical studies. Frye et al. reported a five-drug cocktail (the so-called
‘‘Pittsburgh cocktail’’) containing caffeine, chlorzoxazone, dapsone, debriso-
quine, and mephenytoin for the simultaneous phenotyping of CYP1A2,
CYP2E1, CYP3A, CYP2D6, and CYP2C19 andN-acetyltransferase activities
(Frye et al., 1997). However, the study of CYP2E1 has been less emphasized
and dapsone is a controversial substrate for CYP3A4 due to its lack of
specificity/selectivity. Streetman et al. reported a four-drug cocktail (the so-
called ‘‘Cooperstown cocktail’’) of oral caffeine, omeprazole, dextromethor-
phan, and intravenous midazolam for simultaneous phenotyping of CYP1A2,
CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase
(Streetman et al., 2000). The Cooperstown cocktail focuses on more important
CYP enzymes and the substrate specificity and availability. Zhu et al. reported
a five-drug cocktail, caffeine, chlorzoxazone, mephenytoin, metoprolol, and
midazolam for phenotyping CYP1A2, CYP2E1, CYP2C19, CYP2D6, and
CYP3A4, in which the oral administration of midazolam increases convenience
(Zhu et al., 2001). Blakey et al. also reported a five-drug cocktail of oral
caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlor-
zoxazone (CYP2E1), and midazolam (CYP3A4) for simultaneous phenotyping
of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Blakey et al.,
2004). All of the four cocktail approaches mentioned above were validated to
rule out drug interactions among the probe substrates. Wang et al. also
reported a cocktail approach to evaluate the short-term and long-term effects
TABLE 7.8 Pharmacokinetic parameters of fluticasone nasal spray (200mg once
daily) +7 days with ritonavir (100 mg twice daily).
PK parameter Fluticasone alone Fluticasone + ritonavir Ratio
Cmax(pg/mL) 11.9 318 28
AUC 0–t(pgh/mL) 8.43 3102.6 368
228 REGULATORY CONSIDERATIONS OF DRUG METABOLISM AND DRUG