Biology Reference
In-Depth Information
150 U/kg/week to 15 healthy young volunteers for three weeks. If the hemat-
ocrit exceeded 48%, the next dose was withheld. After discontinuing epoetin
alfa, all urine samples were positive by isoelectric focusing for two days and
approximately 50% were positive for four days.
We have also determined that darbepoetin alfa is detectable in urine for up
to 12 days. A modest single dose (0.40 µg/kg) was detected in eight of nine
subjects for two to four days post-administration and in some subjects for up
to 12 days post-administration. Thus, the detectability of darbepoetin alfa
appears to be similar or longer than that of rHuEPO, which is consistent with
darbepoetin alfa's longer serum half-life [73].
One limitation of detection-time investigations is that they do not necessar-
ily mimic the dosage regimens used by athletes. Typically athletes become
aware of the retrospectivity of a test and adjust their doping schedules so as to
evade detection. In the case of a rapidly evolving new test, like isoelectric
focusing for urinary rHuEPO, athletes are undoubtedly searching for ways to
foil tests as diligently as laboratories are working on improvements to the tests.
Perhaps the athletes who were found to be using darbepoetin alfa at the 2002
Games of Salt Lake did not expect the test to detect it.
Retrospectivity of the urinary isoelectric focusing test
The ability of isoelectric focusing to control the abuse of erythropoietic pro-
teins among athletes is a complex function of dose, dosing regimen, detection
times, urine collection time relative to last dose, and whether or not the test is
announced in advance or a surprise (short-notice or out-of-competition test-
ing). Sport administrators control the testing time and it is generally agreed
that unannounced short-notice testing is the most effective deterrent. The ath-
lete controls the dose and dosing interval, and the ability of the test to detect
erythropoietic proteins is related to the urinary pharmacokinetics of the protein
and the inherent sensitivity of the test. A good test is one that can detect the
erythropoietic proteins for as long as the beneficial effects of the drug are pres-
ent. The interplay of these factors is only beginning to be explored.
The pharmacodynamic effects of erythropoietic proteins that are particular-
ly pertinent in the context of detecting users and that have been studied in
healthy subjects, as opposed to patients with anemia, are the effects on hema-
tocrit, hemoglobin concentration, and VO
2 max
. The effect on VO
2 max
is the
most relevant because it is a direct measure of performance. rHuEPO admin-
istered at doses of 150 to 230 U/kg/week for approximately three weeks pro-
duces an increase of VO
2 max
of 6% to 8%, as expected [39-41]. Only two stud-
ies have monitored VO
2max
after rHuEPO was discontinued. In the first study,
rHuEPO was administered for 25 days (150 U/kg/week), and four weeks after
the last dose, the VO
2 max
determined was not distinguishable from the VO
2 max
of the placebo group [74]. It has been suggested that athletes may use a low-
dose maintenance regimen that is sufficient to maintain the hematocrit just
beneath the 50% health test threshold [40, 67]. To explore the effects of a low-
dose regimen on VO
2 max
, Russell et al. [40] administered rHuEPO for three
