Studies on the Tissue Levels of Antibiotics in Liver Damaged Animals Part II. Frozen-Micro-Autoradiographical Studies on the Experimentally Damaged Mouse Livers

Abstract

In Part I of this study, the results obtained by bioassay (Okubo's band culture method)revealed that the carbenicillin (CBPC) and cefazolin (CEZ) levels were lower, while gentamicin (GM) levels were higher in experimentally damaged rat livers than in normal controls.
In this Part of the study, the accumulation and localization of these antibi otics in damaged livers were directly observed by the micro-autoradiographical method.
Mice, pretreated with a-naphthylisothiocyanate (ANIT) or carbon tetrachloride (CCl₄)received ¹⁴C-benzylpenicillin (¹⁴C-PCG),¹⁴C-CEZ, or ³H-GM intramusclarly. Micro-autoradiography (MAR) was carried out on the liver tissues removed from the mice 30∼60 min. (60120 min, for GM) after injection of the labeled antibiotics.
The results obtained were as follows:
1) ¹⁴C-PCG: In the CCl₄ damaged liver, the accumulation of grains produced by exposure to ¹⁴C-PCG was found to be delayed in the bile duct, but similar in the portal veins and in the hepatic cell regions in comparison with the controls. In the ANIT damaged liver, these grains were fewer in the bile ducts and hepatic cell regions, and more in the portal veins than in the normal liver.
2) ¹⁴C-CEZ: In the CCl₄ damaged liver, the grain accumulation was decreased in the bile ducts and in the hepatic cell regions, but increased in the portal veins. In the ANIT damaged liver every tissue site presented more grains in the experimentals than in the controls.
3) ³H-GM: In the CCl₄ damaged liver, abundant grains were found irregu larly accumulated in the hepatic cell regions around the central veins, where they never accumulate in a normal liver, and later on the grains were seen diffused throughout the whole of the fatty degenerated hepatic cell regions. Already during the early stage, more grains were also found in these bile ducts than in those of the normal Hiver. In the ANIT damaged liver, more grains were found in the Glisson's sheath regions, difusing into the hepatic cell regions, than in the control liver. Besides, it was note-worthy that the grains had accumulated in the spotty necrotic sites of the hepatic cell regions.
Although all three of the antibiotics examined are those which are overwhelmingly excreted through the kidneys without being metabolized in the body, the above mentioned data show that GM completely differs in its kinetics in the damaged liver from CEZ or PCG, as GM is the only one which accumulates there.
Although these findings require further study for interpretation in the clinical field, they may at least warn against the careless administration of aminoglicosides to liver damaged patients, even if not so imperatively as to patients with renal failure.