The mechanism of cyclosporine toxicity induced by clarithromycin.
OBJECTIVE
Recently a number of case reports have described the interaction of clarithromycin with cyclosporine A, resulting in cyclosporine toxicity. This interaction is presumed to take place via the hepatic cytochrome P450 enzyme system.


METHODS
Following a case of cyclosporine toxicity and acute renal failure in a transplant patient started on clarithromycin, we investigated the effect of oral clarithromycin on the hepatic P450 system in five healthy normal male volunteers, by means of the erythromycin breath test.


RESULTS
Cytochrome P4503A (CYP3A) activity was reduced in all subjects by a mean level of 26% following clarithromycin treatment. This would result in a significant reduction in cyclosporine clearance in patients receiving clarithromycin.


CONCLUSIONS
As clarithromycin was shown to inhibit CYP3A activity in all subjects tested, we recommend that a high degree of caution be exercised when clarithromycin is administered to patients receiving cyclosporine therapy or other drugs known to be eliminated by CYP3A-mediated metabolism.
Spicer
S T
ST
Department of Clinical Pharmacology, Westmead Hospital, NSW, Australia.
Liddle
C
C
Chapman
J R
JR
Barclay
P
P
Nankivell
B J
BJ
Thomas
P
P
O'Connell
P J
PJ
D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D001944:Breath Tests; D002250:Carbon Radioisotopes; D017291:Clarithromycin / Q000009:adverse effects* / Q000494:pharmacology; D016572:Cyclosporine / Q000009:adverse effects* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D012016:Reference Values
D000900:Anti-Bacterial Agents; D002250:Carbon Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017291:Clarithromycin