DISPOSITION OF ORAL AZITHROMYCIN IN HUMANS

Background: The oral bioavailability of azithromycin is approximately 37% in healthy subjects; little is known about the disposition of the remaining 63% of the dose. This study attempted to describe the fate o f azithromycin before absorption. Methods: Twelve subjects with ileost omies in place for >1 month were studied in this open-label, randomize d, three-center, two-period, two-treatment crossover study. Subjects r andomly received a single 500 mg intravenous infusion (over 1 hour) or two 250 mg oral capsules after a fast for >12 hours. Blood and ileost omy samples were collected serially after each administration and anal yzed for azithromycin and two metabolites (descladinose and 9a-N-desme thyl metabolites) by HPLC with electrochemical detection. Results: Mea n +/- SD peak concentration values after oral and intravenous administ ration were 0.21 +/- 0.08 and 3.40 +/- 1.12 mu g/ml. Mean values for a rea under the serum concentration versus time curve were 1.27 +/- 0.65 and 7.14 +/- 1.34 mu g . hr/ml, respectively, The absolute bioavailab ility of 16.2% was approximately one-half the value observed previousl y in healthy subjects. Recovery in ileostomy fluid (percent of dose in 24 hours) of azithromycin, descladinose, and 9a-N-desmethyl metabolit es were 13%, 0.5%, and 1% (total, 15%) after intravenous dosing and 47 %, 13%, and 2% (total, 62%) after oral dosing. Total and heal clearanc es were 776 +/- 126 and 158 +/- 63 ml/min after intravenous dosing. Co nclusion: Because more descladinose metabolite was detected after oral dosing, acid degradation of azithromycin before absorption contribute d to some loss in oral bioavailability, Further, ileal clearance (bili ary plus intestinal excretion clearance) in this population represente d 21% of total clearance. Taken together, these data suggest that the cause of low oral bioavailability of azithromycin is the result of inc omplete absorption rather than acid degradation or extensive first-pas s metabolism.