Investigating the barriers to bioavailability of macrolide antibiotics in the rat

Abstract

The aim of this study was to compare the roles of gastrointestinal absorption and hepatic extraction as barriers to oral bioavailability for macrolide antibiotics erythromycin, clarithromycin, roxithromycin and telithromycin. In this study, the in vitro metabolic stability in rat liver microsomes and hepatocytes, as well as the in vivo pharmacokinetics in rats were determined following intravenous, intraportal, oral and intraduodenal routes of administration. Pharmacokinetic parameters were calculated for each compound for each route of administration. In vitro metabolic stability studies point to low intrinsic clearance of the tested macrolides in both microsomes (<1 mL/min/g) and hepatocytes (<1 mL/min/g), indicating good stability. The oral bioavailability in rat was low to moderate (14, 36, 36 and 25% for erythromycin, clarithromycin, roxithromycin and telithromycin, respectively). Upon intraduodenal dosing, the bioavailability increased by 1.3-3-fold, the highest increase being with roxithromycin, suggesting some loss due to gastric instability. Following portal vein administration, no hepatic first pass effect was observed with roxithromycin, less than 10% with telithromycin, and ca. 20 and 25% for clarithromycin and erythromycin. Our data showed that the tested macrolides display good in vitro metabolic stability, as was confirmed in vivo where a low hepatic first pass effect was observed. The limited oral bioavailability is likely due to poor oral absorption and/or intestinal first pass metabolism.

The Lantibiotic NAI-107 Efficiently Rescues Drosophila melanogaster from Infection with Methicillin-Resistant Staphylococcus aureus USA300

“…Previous in vivo findings from rat studies that utilized administration through oral dosing did not observe adverse effects of nisin (54). However, this might be explained by the fact that our study utilized injection into the circulatory system of whole animals, while rats were exposed through oral administration, which inevitably changes the bioavailability and potential adverse effects of a compound (55). Nisin has also been shown to be degraded by proteases in the digestive system (56).…”

Development of an Adult Physiologically Based Pharmacokinetic Model of Solithromycin in Plasma and Epithelial Lining Fluid

“…and by mouth (capsules) of solithromycin (sponsor data (Cempra) on file). Previous studies evaluating the bioavailability of clarithromycin and telithromycin in rats demonstrated that the limited oral bioavailability is primarily due to low intestinal availability rather than first‐pass metabolism in the liver . In addition, grapefruit juice, a selective intestinal CYP3A4 inhibitor, did not significantly affect the oral absorption of clarithromycin or telithromycin .…”

Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin

“…Kato et al reported that CYP3A4 substrates, which have a hepatic intrinsic clearance of 78 μl/min/mg microsomal protein, have low bioavailability because of intestinal first-pass metabolism [22]. The intrinsic metabolic clearances of CAM and TEL in the liver were low (<1 μl/min/mg microsomal protein) [14]. In addition, grapefruit juice, a selective intestinal CYP3A4 inhibitor, did not affect the oral absorption of CAM and TEL [9,24].…”

“…Many studies show that because CAM and TEL are substrates of P-gp and CYP3A4, the oral bioavailability of CAM and TEL increases after concomitant administration of P-gp and CYP3A4 inhibitors such as ketoconazole and itraconazole [8,9]. Recently, Padovan et al reported that, because of the low intrinsic metabolic clearance of CAM and TEL in the liver, metabolic processes in the liver have a small impact on the oral absorption of these antibiotics [14]. However, the involvement of intestinal availability in the oral absorption of CAM and TEL in the presence of efflux transporters remains largely unknown.…”