In a recent manuscript, Cheng et
al1 used the erythromycin breath test (ERMBT)
to show that delavirdine is a potent in vivo inhibitor
of CYP3A4. As is now customary, a single breath sample
is obtained 20 minutes after injection of [14C
N-methyl] erythromycin, and a published equation2
was used to estimate the total radiolabel exhaled during
the hour after injection. However, as previously published
by Turgeon et al., this equation (1) reveals that if
no radiolabel at all is exhaled at 20 minutes, the value
obtained is 0.38% / hour
% C14 exhaled/hr = 43.917 (%C14 exhaled/min at 20 min)
+ 0.38338 (1)
Since the 20 minute time point is generally equal to
the maximum rate of C-14 exhalation, zero exhalation
at 20 minutes should reveal zero activity. To address
this apparent discrepancy, we examined our database
of 120 tests where breath was sampled every 10 minutes
for one hour to estimate the actual 14CO2
production during this time interval. As shown in Figure
1 (dashed line), a linear equation (below) fits
this data well.
y = 45.471x + 0.2779 R2 = 0.9643 (2)
If the line is forced through the origin (not shown),
the equation is simplified to:
y = 49.496x R2 = 0.9542 (3)
However, the relationship is not perfectly linear and
the following binomial equation (Figure
1, solid line) best fits the data:
y = - 65.988 x2 + 54.645x + 0.0377
R2 = 0.9687 (4)
For breath test results within the range usually observed
in people not receiving potent inducers or inhibitors
of CYP3A4 (1.5 - 4.5 %), we have found that all of the
equations above give comparable values. However, with
extreme inhibition, formulas (1) and (2) underestimate
true inhibition and formulas (3) or (4) should be used.
In the manuscript by Cheng et al, the mean baseline
ERMBT result was 2.84 % and the mean maximal inhibition
was reported to be 73.3%, corresponding to a mean inhibited
value of 0.76%. Subtracting the Y intercept in equation
(1) (0.38%) would estimate the maximal inhibition to
be in the range of 85%.
Figure 1
14C-Erythromycin Breath Test 20 min vs 1 hour
Click on picture to enlarge
These calculations have been published as a Letters
to the Editor by David A. Wagner, Clin. Pharm. Ther.
63:129-30, 1998.
References:
1. Cheng CL, Smith DE, Carver PL, et al. Steady state
pharmacokinetics of delavirdine in HIV-positive patients:
Effect on erythromycin breath test. Clin Pharmacol Ther
1997;61:531-543.
2. Turgeon DK, Leichtman AB, Lown
KS, et al. P450 3A activity and cyclosporine dosing
in kidney and heart transplant recipients. Clin Pharmacol
Ther 1994;56:253-260.
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