Aminopyrine test

The structural feature of aminopyrine is similar to antipyrine except that aminopyrine has a substituent (dimethylamino group) at the C-4 position (Fig. 4). The exceptional efficacy of the aminopyrine breath test derives from the presence of multiple N-methyl groups that are readily removed by oxidative N-demethyla-tion. Hence, further oxidation of several formaldehyde molecules produced by demethylation of aminopyrine gives large volumes of labeled COj that is readily quantified. Some of the metabohtes of aminopyrine are given in Fig. 4 [30, 85, 87-90]. 

Markers for Dynamic Hepatic Function Monitoring by Cytosolic Enzyme Activity 

Determination of the level of cytosolic enzymes such as aspartate transaminase, alanine transaminase, and lactate dehydrogenase is part of standard biochemical liver function tests to measure hepatocellular necrosis [2, 101]. Cytosolic enzymes are not subject to genetic variations inherent in microsomal enzyme production. Liver cytosolic enzymes metabolize several molecules, of which galactose and amino acids are typical examples, used for hepatic function tests. 

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Features of the test substance aminopyrine (dimethyl-aminopyrine) are (i.) rapid and complete intestinal resorption, (2.) low protein binding, and (i.) almost exclusive metabolization by the liver. The aminopyrine test is known to be non-invasive, methodologically simple and quick to perform. Of importance is a resting period for the patient of at least 30 minutes prior to the intravenous administration of C-aminopyrine in a dosage of 1.5 fCi. Depending on the liver function, radiation exposure of the patient corresponds to 0.6-2.5 mrem (= 1-2 thorax x-rays). The test is also influenced by numerous medicaments and alcohol as well as any alteration in the basal metabolic rate. The procedure finishes with a triple breath test at ten-minute intervals. 

A number of studies have demonstrated the value of the aminopyrine test. There is a close correlation with histology and prognosis of current liver diseases as well as with the estimation of the operative risk in patients suffering from cirrhosis. Accelerated aminopyrine dissimilation due to toxin-induced microsomal enzyme activation may reveal alcohol or drug abuse even without recognizable liver damage. (51,60,71,75,76,83,86)... 

Agarwal et al. 1978), the quantification of these specific enzymes may indicate that exposure to endosulfan has occurred. Blood tests, such as decay curves for aminopyrine in plasma, which are semiquantitative indices of liver enzyme induction, have been used successfully in the past to demonstrate enzyme induction in pesticide-exposed workers. Because numerous chemicals found at hazardous waste sites also induce these hepatic enzymes, these measurements are not specific for endosulfan exposure. However, measurements of enzyme activity, together with the detection of the parent compound or its metabolites in tissue or excreta, can be useful indicators of exposure. All of these potential biomarkers require further verification in epidemiological studies. Further studies with focus on the development of methods to separate and measure the estrogenicity of endosulfan in in vitro assays would be valuable since these assays are more sensitive and discriminative than other conventional biomarkers. Preliminary results have been presented by Sonnenschein et al. (1995). 

The acute toxicity of emorfazone was found to be equal to or less than that of aminopyrine depending on animal models used [45]. From chronic toxicity tests [46,47], safe doses of 30 mg/kg per day (rats) or 120 mg/kg per day (dogs) were deduced. In rats, no significant effects of (3) on the reproductive activity or newborn development were observed [48-50], nor were adverse effects on the embryos found when (3) was given to rabbits, rats or mice during the period... 

Fig. 3. Relationship between substrate lipophilicity (log P) and ability of screened microorganisms to metabolize model substrates (AP = Aminopyrine DZ = Diazepam TE = Testosterone TH = Theophylline WF = Warfarin). Log P is the logarithm of the partition coefficient of a compound between n-octanol and a pH 7.0 aqueous buffer. Ordinates represent the % of cultures tested able to transform the substrates, independently of the extent of metabolism and number of products formed (from [185])...

In Table 1 is a list of the environmental secondary and tertiary amines which have been tested by feeding to rats together with nitrite. Of these, several react very readily with nitrite in acid solution, but some, for example phenmetrazine (2 , 27), give rise to a noncarcinogenic N-nitroso derivative. On the other hand, aminopyrine reacts extremely readily with nitrous acid, although it is a tertiary amine, and forms the potent carcinogen nitrosodimethylamine in high yield (28, ). The other amines vary considerably in the extent to which they form N-nitroso derivatives by reaction with nitrous acid, especially at the relatively low concentrations which model human exposure more closely... 

Schoeller DA, Kotake AN, Lambert GH, et al. Comparison of the phenacetin and aminopyrine breath tests effect of liver disease, inducers and cobaltous chloride. Hepatology 1985 5 276-281. 

Several tests have been developed to quantify actual liver function, including indocyanine green (ICG), aminopyrine and bromosulpho-thalein. The principle of these tests is to determine whether hepatic blood flow or cell function is reduced by administering a chemical which is exclusively taken up or metabolised by the liver. For example, in the ICG clearance test the ICG is a non-toxic chemical solely taken... 

Giannini E, Fasoli A, Chiarbonello B, et al. (2002) 13C-aminopyrine breath test to evaluate severity of disease in patients with chronic hepatitis C virus infection. Aliment Pharmacol Ther 16 717-725. 

Villeneuve JP, Infante-Rivard C, Ampelas M, et al. (1986) Prognostic value of the aminopyrine breath test in cirrhotic patients. Hepatology 6 928—931. 

Principle After the test substance has been demethylated by the microsomal enzyme system of the SER (cytochrome P 450), the labelled carbon atoms are catabolized to C02. The velocity of demethylation can be measured by determining the C02 value in expired air. Catabolization of aminopyrine is enhanced with elevated activity of the cytochrome P 450 and reduced accordingly due to the loss of liver cell volume. The metabolization is independent of perfusion. Exposure to radiation is minimal. 

Monroe, P.S., Baker, A.L., Schneider, J.F., Krager, P.S., Klein, PJ>., Schoeller, D. The aminopyrine breath test and serum bile acids reflect histologic severity in chronic hepatitis. Hepatology 1982 2 317-322... 

Urbain, D., Muls, V., Thys, O., Ham, H.R. Aminopyrine breath test improver long-term prognostic evaluation in patients with alcoholic cirrhosis in Child class A and B. J. Hepatol. 1995 22 179-183... 

Organic anions of both endogenous and exogenous origin are extracted from the sinusoidal blood, biotransformed, and excreted into the bile or urine. Assessment of this excretory function provides valuable clinical information. The most frequently used tests involve the measurement of plasma concentrations of endogenously produced compounds, such as bilirubin and bile acids, and determination of the rate of clearance of exogenous compounds, such as aminopyrine, lidocaine, and caffeme. 

Xenobiotics are foreign substances that are cleared and metabolized by the liver and some have been used as tests of liver function. For example, certain Hpophilic substances such as bromsulfophthalein (BSP), indocyanine green (ICG), aminopyrine, caffeine, Udocaine, and rose Bengal are excreted into bile as the intact parent compound, its conjugates, or both. The clearance of these xenobiotics by the liver is normally very rapid, and it is beUeved that uptake by hepa-... 

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