The Erythromycin Breath Test (ERMBT)
dose contains 3 µCi of [14C-N-methyl] erythromycin.
Dosimetry data in humans has not been collected because
it predates FDA regulations regarding disposition and
metabolism data. Dosimetry calculations have been based
solely on data obtained in male rats (1,2).
14C Erythromycin distribution and excretion was studied
in 10 rats after intravenous administration of [14C-N-methyl]
erythromycin (1). Erythromycin is rapidly metabolized
in the liver by N-demethylation by the cytochrome enzyme
P450 3A4. The resulting metabolite N-desmethyl-erythromycin
is excreted in bile. The isotopic methyl group is eliminated
in expired air as 14CO2.
After 20 hours of administration of isotopic erythromycin
in rats, about 37-43% of injected radioactivity was
recovered in feces, 27-36% in the urine and 21-29% in
expired air. The half-life of a single intravenously
injected dose of [14C-N-methyl] erythromycin was 6 hours.
There was a general distribution of radioactivity in
various tissues of rats following isotopic erythromycin
administration. Highest concentrations of radioactivity
were found in liver, spleen, pancreas, kidney, adrenals,
submaxillary glands and lungs in addition to urine,
bile, feces and intestinal tract. Lower amounts of radioactivity
were found in skin, fat and brain. Intracellular distribution
studies indicated that erythromycin and its metabolites
were capable of entering various cellular components
of the liver.
The 14C erythromycin dose emits beta radiation to exposed
individuals. The radiation dose estimate for [14C-N-methyl]
erythromycin has been calculated by Dr. Richard Sparks,
Oak Ridge Institute for Science and Education, Radiation
Internal Dose Information Center. The estimate is based
on data gathered in rats and a description of the model
is found in Appendix 1.
The total effective dose equivalent is 2.1 mrem for
a 3 µCi dose of 14C erythromycin (6.9E-01 rem/mCi).
The estimated total effective dose contained in the
ERMBT dose is comparable to about one-quarter of a chest
x-ray and significantly lower than other nuclear medicine
tests (Appendix 2). The
estimated organ radiation exposures are shown in Appendix
3.
References
- Lee, C.C. et al. (1956) J. Pharmacol Exp. Ther.
117:265-273.
- Kibwage I.O. et al. (1989) European J Drug Metab.
and Pharmacokinetics 14:7-14.
Appendix 1
Erythromycin Dosimetry Assumptions
The calculation of the 14C erythromycin
radiation dose estimate in humans is based on data gathered
in rats by Kibwage I. O. et al. (European J. of Drug
Metab. and Pharmacokinetics, 1989 Vol. 14, No. 1. pp.7-14.)
and Lee C.C. et al. (J. Pharmacol. Exp. Ther. 117, 1956,
pp. 265-273.). The model incorporates a 64% absorption
of administered activity from GI tract into the blood,
based on data from Colburn W.A. et al. (Journal of Clinical
Pharmacology 17(10 pt 1)592-600 Oct. 77). The transport
of activity in the GI tract was modeled according to
the ICRP 30 model. The dynamic bladder model with a
4.8-hour voiding interval was used. The radiation dose
estimate was calculated using phantom of Cristy &
Eckerman (Report ORNL/TM-8381/V1 & V7).
Rat data from two sources were folded
together to form a data set for IV administration of
erythromycin. Where possible, these data were extrapolated
to humans using a weight based extrapolation method.
The absorption rate transfer coefficient from the GI
tract to blood that was found in the fitting process
for the IV model, was very similar to the value that
was taken from the literature source for humans, which
was used in the oral model. This coefficient, when used
with the ICRP-30 GI tract model, resulted in 64% of
the erythromycin being absorbed into the bloodstream.
This matches nicely with a separate literature result
of 70% absorption of erythromycin in rats receiving
oral doses of erythromycin. The peak concentration in
plasma found by the model was 1.1 % of the administered
dose. This agrees very nicely with the peak plasma values
for humans found in various literature sources which
averaged about 1.3% of the administered erythromycin.
The doses in the walls of the GI tract
were calculated by adding the absorbed dose caused by
the contents, to the absorbed dose from the activity
within the walls. The effective dose equivalent (EDE)
was corrected by multiplying the absorbed dose from
the activity within the walls by the remainder weighting
factor. The doses to the lachrymal and submaxillary
glands were from self dose only, and these doses were
ignored in the calculation of the EDE.
Appendix 2
Radiation Dosage of the Erythromycin Breath Test Compared
to other Nuclear Tests |
