Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A.
BACKGROUND
Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability, and an in vivo probe to measure such differences would serve several purposes. The erythromycin breath test (ERBT) is an established approach that has proven useful in this regard, but it has several limitations. More recently, the hydroxylation of midazolam has been suggested as an alternative in vivo probe approach, because it is possible to estimate CYP3A activity in the intestinal epithelium as well as in the liver. The purpose of this study was to investigate the relationship, if any, between the ERBT and midazolam's CYP3A-mediated metabolism.


METHODS
Twenty healthy, medication-free young (24 to 46 years) European Americans (10 women) each received on separate days, in random order, either 3 microCi [14C-N-methyl]-erythromycin intravenously, 1 mg midazolam intravenously, or 2 mg midazolam orally. An ERBT value was determined 60 minutes after administration, and clearances were estimated after midazolam administration. In addition, an endogenous 0- to 4-hour urinary 6beta-hydroxycortisol/cortisol ratio was measured.


RESULTS
All three measured drug trait values varied approximately threefold to fivefold, whereas the endogenous phenotype measure exhibited far greater variability (>100-fold). No statistically significant (P < .05) correlations existed between any of the trait values, including the ERBT value, obtained after intravenous administration of the radiolabeled probe and the systemic clearance of midazolam, expressed in terms of either total or unbound drug, or on an absolute or a body weight-corrected basis (r = 0.03 to r = 0.24; P = .08 to P = .90). Substratification according to sex generally did not improve such relationships.


CONCLUSIONS
Although both erythromycin N-demethylation and the metabolism of midazolam by hydroxylation are mediated by CYP3A, the phenotypic trait measures associated with these two in vivo probe drugs do not provide the same information about the catalytic activity of the enzyme. An indirect measure such as the ERBT may reflect CYP3A activity and be useful for some purposes, but the estimation of the oral and intravenous clearance of midazolam has additional advantages, and they may be more applicable and have broader usefulness as quantitative estimates of CYP3A activity.
Kinirons
M T
MT
Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tenn, USA.
O'Shea
D
D
Kim
R B
RB
Groopman
J D
JD
Thummel
K E
KE
Wood
A J
AJ
Wilkinson
G R
GR
D000328:Adult; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004917:Erythromycin / Q000378:metabolism*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D016014:Linear Models; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010641:Phenotype; D011500:Protein Synthesis Inhibitors / Q000378:metabolism*; D012016:Reference Values; D044465:White People / Q000235:genetics
D014151:Anti-Anxiety Agents; D000900:Anti-Bacterial Agents; D011500:Protein Synthesis Inhibitors; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam; D006854:Hydrocortisone