Effect of macrolide antibiotics on uptake of digoxin into rat liver

Abstract

The objective of this study was to examine the effect of macrolide antibiotics, clarithromycin, erythromycin, roxithromycin, josamycin and azithromycin, on the hepatic uptake of digoxin. The uptake of [(3)H]digoxin was studied in rats in vivo, using the tissue-sampling single-injection technique, and in isolated rat hepatocytes in vitro. The uptake of [(3)H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (K(m)) of 445 nM. All the macrolide antibiotics inhibited the uptake of [(3)H]digoxin into rat hepatocytes in a concentration-dependent manner. However, clarithromycin did not affect the in vivo hepatic uptake of digoxin in rats. The in vivo permeability-surface area product of digoxin for hepatic uptake (PS(inf)) was estimated to be 12.5 ml/min/g liver from the present in vitro data, which is far larger than the hepatic blood flow rate (1.4 ml/min/g liver). Macrolide antibiotics at clinically relevant concentrations inhibit digoxin uptake by rat hepatocytes in vitro, but not in vivo, probably because hepatic uptake of digoxin in rats is blood flow-limited. Clinically observed digoxin-macrolide interaction in humans could be due to macrolide inhibition of hepatic digoxin uptake, if the uptake is permeation-limited.

Culture Period-Dependent Changes in the Uptake of Transporter Substrates in Sandwich-Cultured Rat and Human Hepatocytes

“…Because digoxin is an Oatp1a4-specific substrate (Shitara et al, 2002), our result implies that the transport function of Oatp1a4 was greatly reduced during the 96-h culture period required for SCH. In our data, half of the digoxin uptake was dominated by active saturable transport in isolated rat hepatocytes, whereas a previous report indicated that 79% of its uptake was saturable in cultured rat hepatocytes (Ito et al, 2007). The apparent discrepancy may come from the different experimental systems and possible alteration of passive permeability through the inhibition of Na ϩ /K ϩ -ATPase by 100 M digoxin.…”

HEPATOTOXIC IMPACT OF ERYTHROMYCIN SUCCINATE AFTER ORALLY REPEATED EXPOSURE IN MALE ALBINO SWISS MICE (Mus musculus)

“…Measurement of the levels of these enzymes is considered as an indication of the severity of the damage to the liver, as evidenced, for example, by the presence of higher levels of the AST cytoplasmic isoenzyme than those of the mitochondrial isoenzyme. Levels of this enzyme are increased during acute liver diseases (12) and during severe damages in the cells of the kidneys, pancreas, and red blood cells, while levels of ALT and AST increase in association with liver necrosis (9). Table 1.…”