Comparison of the dapsone recovery ratio and the erythromycin breath test as in vivo probes of CYP3A activity in patients with rheumatoid arthritis receiving cyclosporine.
BACKGROUND
Cytochrome P4503A (CYP3A) is primarily responsible for the metabolism of cyclosporine and that of many other drugs. Several substrates of CYP3A have been investigated for use as pharmacologic probes to predict the CYP3A-metabolizing capacity of an individual and, therefore, the disposition of other CYP3A substrate drugs. One such measure of CYP3A activity is the 14C erythromycin breath test, which has been applied to the prediction of cyclosporine disposition. However, the test has practical limitations. Because of this, the 0- to 8-hour urinary dapsone recovery ratio has been studied as an alternative and more practical probe of CYP3A activity.


METHODS
The dapsone recovery ratio and the 14C erythromycin breath test were correlated with cyclosporine concentrations in 16 patients with rheumatoid arthritis to determine the usefulness of the dapsone recovery ratio as an alternative to the 14C erythromycin breath test. The erythromycin breath test showed a fourfold variation between subjects and correlated weakly with trough cyclosporine concentrations (r = -0.50, p < 0.05), whereas the dapsone recovery ratio varied only approximately twofold between subjects and did not correlate with trough cyclosporine concentrations (r = 0.02, p = 0.94). The correlation between the dapsone recovery ratio and the erythromycin breath test (r = 0.22, p = 0.41) was not significant.


CONCLUSIONS
These data suggest that results obtained with one probe in vivo may not apply to another CYP3A substrate. The poor quantitative relationship between cyclosporine concentrations and the erythromycin breath test limits its usefulness in the prediction of an individual's cyclosporine dose requirement.
Stein
C M
CM
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Kinirons
M T
MT
Pincus
T
T
Wilkinson
G R
GR
Wood
A J
AJ
D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000097:blood* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology*; D001944:Breath Tests / Q000379:methods; D002250:Carbon Radioisotopes; D016572:Cyclosporine / Q000097:blood* / Q000627:therapeutic use; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003622:Dapsone / Q000493:pharmacokinetics*; D004917:Erythromycin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011237:Predictive Value of Tests; D011500:Protein Synthesis Inhibitors
D018501:Antirheumatic Agents; D002250:Carbon Radioisotopes; D011500:Protein Synthesis Inhibitors; D004917:Erythromycin; D016572:Cyclosporine; D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1