The effect of ciprofloxacin on theophylline pharmacokinetics in healthy subjects.
1. The mechanism of the interaction between ciprofloxacin and theophylline was investigated in nine healthy subjects. 2. Subjects were given a single oral dose of theophylline (3.4 mg kg-1), before and after 60 h of ciprofloxacin therapy at a dose of 500 mg twice daily. 3. Ciprofloxacin reduced the oral clearance of theophylline by 19% (-7.73 +/- 6.42 ml kg-1 h-1 (95% confidence limits -12.66, -2.79)). Some subjects (group A, n = 4) showed little decrease in clearance (mean 4.4%; -1.6 +/- 0.7 ml kg-1 h-1 (-2.6, 0.5)), whereas others (group B, n = 5) showed a marked decrease (mean 30%; -12.7 +/- 3.7 ml kg-1 h-1 (-17.2, -8.1)). 4. Comparing groups A and B, the decrease in oral clearance of theophylline in group B could not be ascribed to differences in the AUC of ciprofloxacin. Group A subjects showed only slight inhibition of 1-demethylation (-12.8 +/- 5.5% (-21.5, -4.0)), while group B subjects showed a significantly greater inhibition of 1-demethylation (-49.9 +/- 9.8% (-62.1, -37.7)), 3-demethylation (-44.8 +/- 8.6% (-55.4, -34.1)) and 8-hydroxylation (-27.0 +/- 3.7% (-31.6, -22.4)). 5. The results suggest that inter-individual variability in the inhibition of theophylline metabolism by ciprofloxacin can be attributed to inter-individual differences in the level of CYP1A2 expression and/or in the degree of inhibition of hepatic CYP1A2 and CYP3A4. 6. The interaction between ciprofloxacin and theophylline can be clinically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Batty
K T
KT
Department of Pharmacy, Fremantle Hospital, Western Australia.
Davis
T M
TM
Ilett
K F
KF
Dusci
L J
LJ
Langton
S R
SR
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004347:Drug Interactions; D005260:Female; D005454:Fluorescence Polarization; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine
D065607:Cytochrome P-450 Enzyme Inhibitors; D002939:Ciprofloxacin; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human