The effect of ciprofloxacin and clarithromycin on sildenafil oral bioavailability in human volunteers.
Sildenafil is the first oral therapeutic agent for the management of male erectile dysfunction. Its oral bioavailability is only 40% due to extensive presystemic elimination, mainly by CYP3A4. This study examined the effect of coadministration of ciprofloxacin or clarithromycin, which inhibit CYP3A4, on the bioavailability and pharmacokinetics of sildenafil. Twelve healthy male volunteers received sildenafil alone or after pretreatment with the inhibitors in a balanced three-way crossover design. The pharmacokinetic analysis showed that ciprofloxacin coadministration with sildenafil significantly increased the AUC from 1407 +/- 380 to 2986 +/- 917 microg h/l (90% confidence interval 119%-159%) and the Cmax from 287 +/- 67 to 623 +/- 192 microg/l (90% confidence interval 127%-152%). Similarly, clarithromycin coadministration increased sildenafil AUC from 1407 +/- 380 to 3209 +/- 762 microg h/l (90% confidence interval 127%-161%) and Cmax from 287 +/- 67 to 694 +/- 259 microg/l (90% confidence interval 132%-157%). Ciprofloxacin coadministration and clarithromycin coadministration with sildenafil did not affect the rate of sildenafil absorption significantly. These results indicate that coadministration of ciprofloxacin and clarithromycin significantly increased sildenafil bioavailability which can be attributed to the inhibitory effect of ciprofloxacin and clarithromycin on CYP3A4. Dose adjustment of sildenafil is thus necessary when administered with such drugs.
Hedaya
Mohsen A
MA
Department of Clinical Pharmacy, College of Pharmacy, University of Tanta, Tanta, Egypt. mhedaya@e-pharmacokinetics.com
El-Afify
Dalia R
DR
El-Maghraby
Gamal M
GM
D000284:Administration, Oral; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001682:Biological Availability; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000494:pharmacology*; D017291:Clarithromycin / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones
D000890:Anti-Infective Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D002939:Ciprofloxacin; D003577:Cytochrome P-450 Enzyme System; D000068677:Sildenafil Citrate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin