Metabolism, Studies

In addition to peptide-based studies, degradation and absorption kinetics of a homologous series of acyclovir ester prodrugs have been studied using the in situ perfusion model [25, 26], The studies showed that due to high esterase activity of the rat nasal mucosa (96% disappearance of hexanoate prodrug of acyclovir in 960 min), the rat in situ model is an acceptable model to screen the nasal absorption of prodrugs. 

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As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

It is hoped that these volumes will be useful not only to the chemist who wishes to carry out synthesis in the steroid field, but also to the broader group of organic chemists who are interested in carrying out selective and stereo-chemically defined reactions, as well as protective chemistry on extraneous functional groups, during a broad range of synthetic applications. The chapter on the introduction of deuterium and by inference tritium into steroids was included because of the importance of this technique in mechanistic and metabolic studies both in the steroid and nonsteroid field. 

Properties of Radioactive and Stable as Tracers in Metabolic Studies Heavy Isotopes Used... 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

Dawson, M.J., Gadian, D.G., Wilkie, D.R. (1980). Mechanical relaxation rate and metabolism studied in fatiguing muscle by phosphorus nuclear magnetic resonance. J. Physiol. 299,465-484. 

One approach to drug metabolism studies is therefore to predict the molecular weights of possible metabolites of the drug under consideration, to use reconstructed ion chromatograms to locate any components that have the appropriate molecular weights and then use MS-MS to effect fragmentation of the (M - - H)+ ions from these metabolites, and then to finally link the m jz values of the ions observed with ions of known structure from the parent drug or from other metabolites whose structures have been elucidated. 

A slightly different use of accurate mass measurement in drug metabolism studies has been reported [31]. In this investigation, the accurate masses of the ions derived from Glyburide (Figure 5.48) and some of its metabolites were used to calculate the difference in mass, and thus the elemental composition, between certain of the ions observed in the spectra of the various compounds. 

Gagne J, Brodeur J. 1972. Metabolic studies on the mechanism of increased susceptibility of weanling rats to parathion. Can J Physiol Pharmacol 50 902-915. 

Carroll SS, Olsen DB (2006) Nucleoside analog inhibitors of hepatitis C vims rephcation. Infect Disord Dmg Targets (Formerly Current Drag Targets - Infectious) 6 17-29 CasteU JV, lover R, Martinez-Jimenez CP, Gomez-Lechon MJ (2006) Hepatocyte cell lines their use, scope and limitations in dmg metabolism studies. Expert Opin Drag Metab Toxicol 2 183-212... 

The results of metabolism studies with laboratory animals and livestock indicate that endosulfan does not bioconcentrate in fatty tissues and milk. Lactating sheep administered radiolabeled endosulfan produced milk containing less than 2% of the label. Endosulfan sulfate was the major metabolite in milk (Gorbach et al. 1968). A half-life of about 4 days was reported for endosulfan metabolites in milk from survivors of a dairy herd accidentally exposed to acutely toxic concentrations of endosulfan endosulfan sulfate accounted for the bulk of the residues detected in the milk (Braun and Lobb 1976). No endosulfan residues were detected in the fatty tissue of beef cattle grazed on endosulfan-treated pastures for 31-36 days (detection limits of 10 ppm for endosulfan, 40 ppm for endosulfan diol) the animals began grazing 7 days after treatment of the pastures. Some residues were detected in the fatty tissue of one animal administered 1.1 mg/kg/day of endosulfan in the diet for 60 days. No endosulfan residues were... 

Klasson-Wehler, E. (1989). Synthesis of Some Radiolabelled Organochlorines and Metabolism Studies in Vivo of Two PCBs, doctoral dissertation. University of Stockholm, Sweden. 

Hanashiro PK, Weil MH Anaphylactic shock in man. Report of two cases with detailed hemodynamic and metabolic studies. Arch Intern Med 1967 119 129. 

Anari MR, Sanchez RI, Bakhtiar R, Franklin RB, Baillie TA. Integration of knowledge-based metabolic predictions with liquid chromatography data-dependent tandem mass spectrometry for drug metabolism studies application to studies on the biotransformation of indinavir. Anal Chem 2004 76 823-32. 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

The purpose of the discussion of alternative pathways of nitrosamine activation (alternative to the a-hydroxylation hypothesis) is to demonstrate how fundamental organic chemistry may help classical metabolism studies to provide clues... 

Cyclic nitrosamines are among the most potent and environmentally significant nitrosamine carcinogens. Like the acyclic nitrosamines, metabolism is necessary for their carcinogenicity. Elucidation of the specific metabolic pathways of cyclic nitrosamine activation and detoxification is a challenging problem, and considerable progress has been achieved in recent years. In this chapter, we will review metabolic studies on N-nitrosopyrrolidine (NPYR), N -nitrosonornicotine (NNN), N-nitrosopiperidine (NPIP), N-nitrosohexamethyleneimine (NHEX), N-nitrosomorpholine (NMOR),... 

Only limited metabolic studies have been carried out on NPIP. It undergoes a-hydroxylation by rat liver microsomes to give 5-hydroxypentanal, a process analogous to the formation of... 

Lack of repeatability of the results of metabolic studies using laboratory strains that have been maintained by repeated transfer for long periods under nonselective conditions may be encountered. These strains may no longer retain their original metabolic capabilities, and this may be particularly prevalent when the strains carry catabolic plasmids that may have been lost under nonselective conditions. For these reasons, strains should be maintained in the presence of a cryoprotectant such as glycerol at low temperatures (-70°C or in liquid Nj) as soon as possible after isolation. Freeze-drying is also widely adopted, and is recommended. 

Although the radioactive isotope H has been extensively used for studies on the uptake of xenobiotics into whole cells, the intrusion of exchange reactions and the large isotope effect renders this isotope rather less straightforward for metabolic studies. Both deuterium H-labeled substrates, and oxygen and OH2 have, however, been extensively used in metabolic studies, since essentially pure labeled compounds are readily available and mass spectrometer facilities have become an essential part of structural determination. 

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