Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction.
In this study the drug interaction between ciprofloxacin (CIPRO) and pentoxifylline (PTX) was investigated and the role of CYP1A2 in the drug interaction was determined with the aid of a selective CYP1A2 inhibitor, furafylline (FURA), and the Cyp1A2 knockout mouse. Serum concentrations of PTX (83.4+/-1 micromol/l) and metabolite-1 (M-1) (13.7+/-2.8 micromol/l) following a single injection of PTX (100 mg/kg i.p.) were significantly higher (P<0.05) in mice treated with CIPRO (25 mg/kg i.p. 9 days) compared to serum concentrations of PTX (46.3+/-0.5 micromol/l) and M-1 (6.4+/-1.1 micromol/l) in mice administered saline. Murine hepatic microsomes were incubated with PTX alone or the combination of PTX and CIPRO. The metabolism of PTX in the murine hepatic microsomes containing both CIPRO and PTX was significantly decreased compared to microsomes incubated with PTX alone, suggesting that CIPRO may inhibit the metabolism of PTX. To further clarify the role of CYP1A2 in the metabolism of PTX in mice, the effect of a selective CYP1A2 mechanism based inhibitor, FURA, on the metabolism of PTX was investigated and our results indicate that FURA inhibited metabolism of PTX. We then investigated PTX elimination in the Cyp1A2 knockout mouse. Blood levels of PTX were assessed at 2 and 20 min following a single injection of PTX (32 mg/kg i.v). Serum concentration of PTX was determined in Cyp1A2 knockout mice compared to Cyp1A2 wild type control mice. The serum concentration of PTX in Cyp1A2 wild type mice (n=9) was 22.2+/-3.2 micromol/l at 20 min following injection of PTX. The serum concentration of PTX in Cyp1A2 knockout mice (n=11) was significantly elevated at 20 min following injection of PTX compared to Cyp1A2 wild type mice. These results clearly indicate that inhibition of CYP1A2 catalytic activity that occurs in the Cyp1A2 knockout mice is sufficient to alter metabolism of PTX and result in markedly elevated levels in serum of Cyp1A2 knockout mice. The results of Western analysis in murine microsomes suggest that CYP1A2 protein levels were not altered by CIPRO indicating that CIPRO did not downregulate Cyp1A2. The results of Western analysis also indicated that CIPRO treatment increased CYP2E1 in mouse microsomes and the implications of these will be discussed.
Peterson
Theresa C
TC
Department of Medicine, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada. tcpmed@dal.ca
Peterson
Marc R
MR
Wornell
Philip A
PA
Blanchard
Matthew G
MG
Gonzalez
Frank J
FJ
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D015153:Blotting, Western; D002939:Ciprofloxacin / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010431:Pentoxifylline / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D002939:Ciprofloxacin; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; D037342:Pertussis Toxin; D010431:Pentoxifylline