Microsomes renal

Intestinal absorption of digoxin is less complete compared to digitoxin. In order to improve absorption, acetylated- and methylated-digoxin derivates were developed. Digitoxin is metabolised in hepatic microsomal enzymes and can be cleared independently from renal function. The therapeutical serum level of digoxin is 0.5-2.0 ng/ml and 10-35 ng/ml of digitoxin. Steady state plateau of therapeutic plasma concentrations is reached after 4-5 half-life-times using standard daily doses [5]. 

As described above, it will be normal to assume that the dose interval is 24 hours, i.e., once-a-day dosing. Absorption can be estimated with good confidence from absorption in the rat (see Section 6.1). Clearance is the sum of the predicted hepatic, renal, biliary and extrahepatic clearance. Hepatic clearance can be derived from in vitro studies with the appropriate human system, using either microsomes or hepatocytes. We prefer to use an approach based on that described by Houston and Carlile [83], Renal clearance can be predicted allometrically (see section 6.8.1). The other two potential methods of clearance are difficult to predict. To minimize the risks, animal studies can be used to select compounds that show little or no potential for clearance by these routes. As volume can be predicted from that measured in the dog, after correction for human and dog plasma protein binding (see Section 6.2), it is possible to make predictions for all of the important parameters necessary. 

This model integrates existing in vitro data, such as Caco-2 permeability (Papp) and metabolic stability in liver S9 or microsomes, to estimate bioavailability as being either low, medium, or high. Oral bioavailability predictions for not only humans but also other species can be made by using the metabolic stability values of drugs in liver microsomal enzyme preparations from that species. A premise of this model is that metabolic clearance is more important than renal or biliary clearance in determining bioavailability. However, despite the lack of in vitro renal... 

Pawar SS, Kachole MS. 1978. Hepatic and renal microsomal electron transport reactions in endrin treated female guinea pigs. Bull Environ Contam Toxicol 20 199-205. 

Bend, J.R., Pohl, R.J., Davidson, N.P. and Fouts, J.R. Response of hepatic and renal microsomal mixed-function oxidases in the little skate, Ra.ja erinacea, to pretreatment with 3-methyl-cholanthrene or TCDD (2,3,7,8-tetrachlorodibenzo- -dioxin). Bull. Mt, Desert Is. Biol. 

L. B. LaCagnin, P. Lutsie, H. D. Colby, Conversion of Spironolactone to 7a-Thiome-thylspironolactone by Hepatic and Renal Microsomes , Biochem. Pharmacol. 1987, 36, 3439-3444. 

Metabolic pathways of chloroform biotransformation are shown in Figure 2-3. Metabolism studies indicated that chloroform was, in part, exhaled from the lungs or was converted by oxidative dehydrochlorination of its carbon-hydrogen bond to form phosgene (Pohl et al. 1981 Stevens and Anders 1981). This reaction was mediated by cytochrome P-450 and was observed in the liver and kidneys (Ade et al. 1994 Branchfiower et al. 1984 Smith et al. 1984). In renal cortex microsomes of... 

Smith JH, Hook JB. 1984. Mechanism of chloroform nephrotoxicity. III. Renal and hepatic microsomal metabolism of chloroform in mice. Toxicol Appl Pharmacol 73 511-524. 

Clearance of nicotine is decreased in the elderly (age >65) compared to adults (Molander et al. 2001). Total clearance was lower by 23%, and renal clearance lower by 49% in the elderly compared to yonng adults. Lower nicotine metabolism in the elderly may be contribnted to by rednced liver blood flow, since no decrease in CYP2A6 protein levels or nicotine metabolism in liver microsomes due to age has been detected (Messina et al. 1997). No differences in steady-state nicotine plasma levels or estimated plasma clearance valnes were detected in three age gronps (18-39, 40-59, and 60-69 years) nsing patches with the same nicotine content (Gonrlay and Benowitz 1996). The volnme of distribntion of nicotine is lower in older snbjects due to a decrease in lean body mass (Molander et al. 2001). 

Hepatic metabolism and excretion in the bile play major roles in the elimination of both vinblastine and vincristine in humans (52) small amounts of vincristine and vinblastine, of the order of 10% of the administered dose, are excreted unchanged in urine. Renal clearance of vinblastine has been reported to be less than 10% of total serum clearance 53). Vinblastine has been reported to inhibit a polymorphic cytochrome P-450 system in human hepatic microsomes, but the concentrations required were much higher than those observed in clinical settings (54). 

The balance between renal clearance and metabohsm is readily predicted by physicochemical properties [36]. Rate of metabolism and formation of metabolic products can be screened for, using Ever microsomal systems and mass spectrometry. The... 

There are many dipeptidases [EC 3.4.13.x]. Cytosol nonspecific dipeptidase [EC 3.4.13.18] (also referred to as peptidase A, glycylglycine dipeptidase, glycylleucine dipeptidase, and A -)3-alanylarginine dipeptidase) catalyzes the hydrolysis of dipeptides. Membrane dipeptidase [EC 3.1.13.19] (also known as microsomal dipeptidase, renal dipeptidase, and dehydropeptidase I) is a zinc-dependent enzyme (a member of the peptidase family M19) that also catalyzes the hydrolysis of dipeptides. 

A treatment of rutaecarpine causes an increase in renal microsomal enzymes related to CYPIA and enhances the activity and protein levels of CYPIA. It is known that caffeine is a mild stimulant. It is metabolized in the hver by... 

The analysis was completed for 12 compounds for which protein binding, renal and hepatic clearances and microsomal data were available. Plasma concentration versus time profiles in the rat were also available for these compounds. The approach taken was to simulate the individual processes (metabolic clearance, renal clearance, distribution, pharmacological activity). The ability of the PBPK model to simulate the in vivo behavior of the compound was verified in the rat. Thus, the metabolic clearance of the compounds could be reasonably well simulated, based on microsomal data and assuming no binding to microsomes less than twofold deviation between the observed and predicted clearance was achieved for about eight of the... 

Many other cases of carbon tetrachloride-induced hepatic and/or renal injury associated with ethanol ingestion have been described in the medical literature (Durden and Chipman 1967 Guild et al. 1958 Jennings 1955 Lamson et al. 1928 Markham 1967 Tracey and Sherlock 1968). These clinical reports establish that occasional or frequent ingestion of alcoholic beverages can increase the danger from relatively moderate carbon tetrachloride exposure. As ethanol is known to induce microsomal mixed-function oxidase activity in man (Rubin and Lieber 1968), the mechanism of potentiation may involve ethanol-induced enhancement of the metabolic activation of carbon tetrachloride. 

Renal cytosol and microsomes Ni Ultracentrifugation, Liquid scintillation counting 50)... 

Inhibits hepatic microsomal drug-metabolizing enzymes. (Ranitidine, famotidine, and nizatidine do not.) May inhibit the renal tubular secretion of weak bases. 

McCormack KM, Kluwe WM, Rickert DE, et al. 1978. Renal and hepatic microsomal enzyme stimulation and renal function following three months of dietary exposure to polybrominated biphenyls. Toxicol Appl Pharmacol 44 539-553. 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Variations in the tissue expression of CYP2E1 appear to underlie the tissue selectivity of vinylidene chloride toxicity. A sex difference in CYP2E1-mediated metabolism of vinylidene chloride correlates with the incidence of renal tumours (Speerschneider Dekant, 1995). Metabolism in kidney microsomes from male mice was at least six times that in females, while tumours were seen only in males (see Section 3). CYP2E1 could not be detected in rat kidney and no renal tumours were seen in this species. In addition. 

Pentachloroethane given to rats by gavage during a two-year study caused chronic, diffuse kidney inflammation and renal papilla mineralization. A single dose also reduced hepatic cytochrome P450 content and microsomal epoxide hydrolase activities. Inhalation exposure of rabbits to pentachloroethane decreased their total antibody titres (lARC, 1986). 

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