Autoradiographic and biochemical studies of drug distribution in the liver I. [14C] Dehydrocorydaline

Abstract

Whole body autoradiography revealed that the distribution pattern of [14C]dehydrocorydaline in the mouse and rat liver was heterogeneous (or reticular) regardless of time after intravenous administration of the labeled agent. Microautoradiography by dry-mounting method revealed that the macroscopic heterogeneous pattern was due to the periportal localization of the radioactive compound in the hepatic lobule. By comparison with [14C]salicylid acid, [14C]diphenylhydantoin and [14C]p-chlorophenoxyacetic acid whose distribution pattern are homogeneous in the liver, the present studies indicated that the existence and persistence of heterogeneous distribution of [14C]dehydrocorydaline in the liver had the following causes: 1. Shortly after intravenous administration, the amount of [14C]dehydrocorydaline circulated to the liver was greatly restricted by its significant distribution in non-hepatic tissues. This was shown by the whole body autoradiography, radiometry of tissues and quantitative comparison of volumes of distribution in non-hepatic tissues. Therefore, 2. perilobular hepatocytes alone could take up [14C]dehydrocorydaline and consequently, centrilobular cells were unavailable to it: heterogeneous distribution pattern is formed. This was shown by microautoradiography as described above, and by the rapid and significant uptake of [14C]dehydrocorydaline by isolated hepatocytes in vitro and by the liver to which the labeled agents were continuously administered in situ. It was also substantiated by the more homogeneous distribution pattern in the liver of the rat to which greater amount of [14C]dehydrocorydaline was gradually given into the portal vein and of the mouse with allyl formate-induced perilobular damage. 3. Redistribution of [14C]dehydrocorydaline scarcely occurred in the whole body and therefore radioactive substance was not significantly supplied to the liver: the distribution pattern remained unchanged. This was shown by the whole body autoradiography and radiometry of tissues.

Hepatocyte Heterogeneity in Bile Formation and Hepatobiliary Transport of Drugs

“…Such a process was observed earlier, although to a lesser extent, for other bivalent compounds and is in line with their lysosomal accumulation and persistent storage [75][76][77], The zonal distribution is mainly perivenous due to the Also for acridine orange [21,34,47], pro pranolol [105], the alkaloid dehydrocorydal ine [106], chloropromazine and imipramine [107], steep gradients are observed in ante grade perfusions. Although retrograde perfu sions and quantification of the gradients are missing, probably this heterogeneity is, as for rhodamine B, due to the very efficient up take of these lipophilic cations.…”

“…Although retrograde perfu sions and quantification of the gradients are missing, probably this heterogeneity is, as for rhodamine B, due to the very efficient up take of these lipophilic cations. Aminotriazole showed a much lower extraction and no clear acinar gradient was seen shortly after injection [108], For the type-I and type-II model compounds, no studies concerning the acinar heterogeneity in uptake are known yet.…”

Autoradiographic and biochemical studies of drug distribution in the liver III. [14C] Aminotriazole

“…Thus the distribution pattern of [I4C]aminotriazole changed froni homogeneous to heterogeneous with time, differing from previous ['4C]dehydrocorydaline, [3sS]chlorpromazine and [I4C]imipramine (7,8). It was impossible to distinguish macroscopically whether or not the pattern was perilobular as in the case of the previous labeld compounds.…”

“…PORTAL VEIN localized in the perilobular areas (7,8), (I4C]aminotriazole was in centrilobular areas, which also resulted in a heterogeneous distribution pattern as seen macroscopically. This finding suggests that the distribution pattern of (I4C]aminotriazole is due to a different mechanism than that for the previous compounds.…”

“…I and 4) is occasionally observed by macroautoradiography after administration of certain radiolabeled compounds (1-6). In previous papers (7,8), we have shown that predominant localization of radioactive compounds in periportal regions of hepatic lobules results in the rare pattern in macroscopic aspects. The pattern either changes to a homogeneous one or remains unchanged with time dependently on pharmacokinetic properties of the labeled compound.…”