Abstract
Among any drugs, no comparative pharmacological study on how prodrug and its active metabolite behave in animal bodies is available. Immunohistochemistry (IHCs) using newly prepared two monoclonal antibodies, AOS‐96 and AOC‐160, monospecific for oseltamivir (OS) and its metabolite oseltamivir carboxylate (OC) were developed, simultaneously detecting the uptake or excretion of OS and OC in the intestine, liver, and kidney of rats to which OS was orally administered. In the intestine, IHC for OS revealed OS highly distributed to the absorptive epithelia with heavily stained cytoplasmic small granules (CSGs). IHC for OC showed that OC also distributed highly in the epithelia, but without CSGs, suggesting that OS was partly converted to OC in the cells. In the liver, OS distributed in the hepatocytes and on their bile capillaries, as well as on the lumina from the bile capillaries to the interlobular bile ducts. OC distributed in the whole cell of the hepatocytes, but without CSGs nor on any lumina through the interlobular bile ducts. In the kidney, a few levels of OS distributed in the cytoplasm of almost all the renal tubule cells, but they contained numerous CSGs. In contrast, OC distributed highly in the proximal tubules, but very slightly in the lower renal tubules of the nephrons. Thus, it was concluded that the two drugs behave in completely different ways in rat bodies. This paper also discusses a possibility of the correlation of OS or OC levels in tissue cells with their known transporters.
Highlights
There were no reports available on IHC for drugs developed by pharmacologists or histologists until 2005.9 Prior to our starting to investigate IHC for drugs, we had been engaged in the research for low molecular weight endogenous amines, polyamines,[10] and histamine,[11] by IHC procedure, in which Abs specific for their amines were prepared and used with light and electron microscopy
The AOS-96 and anti-oseltamivir carboxylate (AOC)-160 anti-OS monoclonal antibody (mAb) were demonstrated to be monospecific for OS and oseltamivir carboxylate (OC) with no cross-reaction with OC and OS, respectively, and unrelated compounds by the inhibition and binding enzyme-linked immunosorbent assay (ELISA) (Figure 1Ba, b and Ca, b)
No antibody activity against the carrier bovine serum albumin (BSA) or GA-BSA was evident, demonstrating a lack of recognition. These results strongly suggest that the AOS-96 and AOC-160 mAbs recognize the OS and OC molecules, respectively, and, in part, carrier protein-conjugation site(s) of GA, and that both of these mAbs can precisely distinguish the differences in the terminal structures of the ethyl ester group of OS and hydrolyzed carboxylate group of OC, respectively
Summary
Oseltamivir (OS) is an ethyl ester-type pro-drug of Ro 64-0802 (oseltamivir carboxylate; OC), a potent and selective inhibitor of viral neuraminidase, a key enzyme involved in the release of the influenza virus from infected host cells.[1,2] OS is used for the prevention, treatment, and prophylaxis of epidemic seasonal influenza of Influenza virus A and B.3 An ethyl ester group of OS is enzymatically cleaved to the active metabolite OC predominantly in the plasma in rats,[4] while in humans (and monkeys), the cleavage takes place in the liver,[5] and both OS and OC are found in the blood.[6,7] The accurate localization of OS and OC in tissue cells would help to develop better understanding of the biological response to the drugs in the pharmacological studies.
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