In vivo comparison of putative probes of CYP3A4/5 activity: erythromycin, dextromethorphan, and verapamil.
OBJECTIVE
Multiple in vivo CYP3A4/5 probes have been proposed. We compared verapamil clearance measures (CYP3A4/5 substrate) to the erythromycin breath test (ERBT) and the cumulative urinary dextromethorphan/3-methoxymorphinan test.


METHODS
Clearance of intravenous and oral racemic verapamil and the area under the plasma concentration versus time curve (AUC) ratio of norverapamil (N-demethylated metabolite) to verapamil after oral verapamil dosing, the ERBT, and the dextromethorphan urinary metabolite ratios were measured in 84 healthy nonsmoking subjects (42 men and 42 women; age, 47 +/- 23 (mean +/- SD) years; weight, 69 +/- 11 kg). Relationships between putative CYP3A4/5 probes were assessed by linear regression.


RESULTS
The strongest correlation was between intravenous and oral verapamil clearance (r2 = 0.26; P = .0001). Relationships between cumulative urinary dextromethorphan/3-methoxymorphinan and (1) intravenous verapamil clearance (r2 = 0.073; P = .024), (2) oral verapamil clearance (r2 = 0.144; P = .001), and (3) plasma AUC(norverapamil)/AUC(verapamil) after oral verapamil (r2 = 0.10; P = .01) were also detected. The ERBT and intravenous verapamil clearance were weakly related (r2 = 0.04; P = .067). No relationship was detected between ERBT and dextromethorphan/3-methoxymorphinan ratios (r2 = 0.00006; P = .945), oral verapamil clearance (r2 = 0.00006; P = .94), or plasma AUC(norverapamil)/AUC(verapamil) after oral verapamil (r2 = 0.0002; P = .9).


CONCLUSIONS
Intravenous and oral verapamil clearance values were significantly correlated, and cumulative dextromethorphan/3-methoxymorphinan urinary ratios correlated with both plasma AUC(norverapamil)/AUC(verapamil) after oral verapamil dosing and with oral and intravenous verapamil clearance. The ERBT correlated only weakly with intravenous verapamil clearance. Results with verapamil are comparable to results with other intravenous and oral CYP3A4/5 probes. Lack of correlation between putative CYP3A4/5 probe results may be attributable to the route of administration; probe characteristics; and intersubject, intrasubject, between-day, and testing measurement variability.
Krecic-Shepard
M E
ME
Division of Clinical Pharmacology and Geriatric Medicine, Northwestern University, Chicago, Ill 60611, USA. m-shepard@nwu.edu
Barnas
C R
CR
Slimko
J
J
Gorski
J C
JC
Wainer
I W
IW
Schwartz
J B
JB
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000889:Anti-Arrhythmia Agents / Q000097:blood; D000900:Anti-Bacterial Agents / Q000378:metabolism; D000996:Antitussive Agents / Q000652:urine; D019540:Area Under Curve; D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000652:urine*; D004917:Erythromycin / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D012016:Reference Values; D014700:Verapamil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood*
D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D000996:Antitussive Agents; D004917:Erythromycin; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; C016904:norverapamil; D014700:Verapamil; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human