The pharmacokinetics of azithromycin and their clinical significance

Abstract

The usefulness of erythromycin is limited by its poor pharmacokinetic profile which is characterised by low blood levels and poor gastric acid stability. Erythromycin's short half-life means that a four-times daily dosage schedule is required for effective treatment. In comparison, the azalide structure of azithromycin confers a much improved pharmacokinetic profile. The bioavailability of azithromycin is approximately 37 % in humans (25 % for erythromycin). Serum concentrations decline in a polyphasic manner and the relatively short serum half-life (11–14 hours recorded 8–24 hours after last dose) is an indication of the initial rapid distribution of drug into the tissues. The low serum levels recorded 24 hours or more after the end of administration are thought to reflect the slow release of azithromycin from tissues. Tissue concentrations exceed serum concentrations by as much as 100-fold following a single 500 mg oral dose. Macrophages and polymorphonuclear leucocytes concentrate azithromycin at levels greater than those found in tissues themselves. During multiple dosing, tissue half-life increases with duration of administration and the tissue to serum ratio further increases. High concentrations of drug are found in tissues such as tonsil, lung, prostate, liver and lymph nodes with relatively low concentrations in fat and muscle. Significantly, the sustained high levels of drug in the tissues appears to correlate with good in vivo activity. Two 1.5 g regimens have been investigated in clinical trials: 500 mg on day 1, followed by 250 mg daily on days 2 to 5; or 500 mg daily for three days. These regimens are expected to maintain azithromycin levels in tissue sites of infection above the MIC for many clinically significant pathogens, and to continue to do so for several days after administration has ceased. In addition, single-dose (1 g) azithromycin has demonstrated excellent clinical efficacy in the therapy of chlamydial urethritis/cervicitis, the high and prolonged tissue levels of antibiotic enabling such a regimen to be effective.