Active metabolite detection

No changes in GTP and y-GT activity were recorded after repeated administration of the above compounds. Also, histopathological examination did not point to liver necrosis. Similar phenomenon detected earlier after repeated administration of monobromobenzene, was interpreted as a result of damage of the microsomal enzymatic system responsible for the appearance of active metabolites (ref. 22). 

The results do not differentiate between C activity derived from TCDD and that of possible metabolites. However, small amounts of C activity were detected in the expired air and urine within the first 10 days following administration. This is evidence that some metabolic alteration or breakdown of TCDD occurs. 

The formation of 0-seryl or 0-prolyl esters (Figure 1) of certain N-hydroxy arylamines has been inferred from the observations that highly reactive intermediates can be generated in vitro by incubation with ATP, serine or proline, and the corresponding aminoacyl tRNA synthetases (11,12,119). For example, activation of N-hydroxy-4-aminoquinoline-l-oxide (119,120), N-hydroxy-4-aminoazobenzene (11) and N-hydroxy-Trp-P-2 (121) to nucleic acid-bound products was demonstrated using seryl-tRNA synthetase from yeast or rat ascites hepatoma cells. More recently, hepatic cytosolic prolyl-, but not seryl-, tRNA synthetase was shown to activate N-hydroxy-Trp-P-2 (12) however, no activation was detectable for the N-hydroxy metabolites of AF, 3,2 -dimethyl-4-aminobiphenyl, or N -acetylbenzidine (122). 

The ventilated and perfused human lung lobe was used as described by Linder and co-workers [74], A twofold difference in the appearance of drug and metabolites in the perfusate was found for the two formulations. Small fractions of the applied dose of BDP were immediately detectable in the perfusate and the amount of the major metabolite, beclomethasone-17-propionate (17-BMP), increased over the experimental period. These observations were similar to the clinical observations that BDP is detected rapidly in the plasma after inhalation and that the appearance of the active metabolite 17-BMP occurs rapidly. The kinetic differences between the formulations were explained on the basis of particle size effects with the conclusion that the discriminatory value of this system to examine the lung pharmacokinetics of inhaled medicines in the absence of systemic effects such as hepatic metabolism was apparent. 

Once in the blood stream, cocaine levels quickly rise in the brain, faster than plasma levels, which then redistribute to other tissues. Cocaine is rapidly metabolized in the blood and liver, with a half-life of 30 to 90 minutes. The major metabolites have a half-life of approximately 8 hours. Although cocaine itself is detected in urine for only 12 hours, the metabolite benzoylecgonine can be detected in urine for at least 48 hours and sometimes up to 2 weeks. Concurrent use of cocaine and ethanol produces an ethyl ester of benzoylecgonine called cocaethylene. Cocaethylene is an active metabolite, blocking dopamine reuptake, and potentiating the effect of cocaine. Thus, concurrent use of cocaine and ethanol can further increase the additional effects of the drugs and the risk of dependency. 

The active constituents of amanita, and perhaps active metabolites as well, are excreted in urine. Because the mushrooms can be very expensive, many Siberian tribesmen drink their urine to prolong intoxication. Both ibotenic acid and muscimol are detected in urine. Up to 27% of muscimol injected into mice has been recovered from urine. 

Recently, three papers have reported the determination of risperidone and its active metabolite 9-hydroxyrisperidone using LLE and SPE technologies. The analytical columns used to separate these compounds were C4 or C18 bonded phases of 3 pm or 5 pm particle sizes with UV/VIS detection. Mobile phases consisted of phosphate bufiers (pH 3-4) in acetonitrile. The sample volumes used ranged from 200 pi to 1 ml, with extraction recoveries averaging 90%. The limits of quantitation ranged from 0.5 to 10 ng/ml in human plasma (Nagasaki et al., 1999 Avenso et al., 2000 Titier et al., 2002). A study by Titier showed the simultaneous determination of clozapine, olanzapine, haloperidol, risperidone, and its active metabolites by RP-HPLC in human plasma. The assay involved LLE with a hexane/isoamyl alcohol mixture... 

In SUMMARY, it would appear that a detailed knowledge of the pharmacokinetics of the main groups of psychotropic drugs is only of very limited clinical use. This is due to limitations in the methods for the detection of some drugs (e.g. the neuroleptics), the presence of active metabolites which make an important contribution to the therapeutic effect, particularly after chronic administration (e.g. many antidepressants, neuroleptics and anxiolytics), and the lack of a direct correlation between the plasma concentration of the drug and its therapeutic effect. Perhaps the only real advances will be made in this area with the development of brain imaging techniques whereby the concentrations of the active drug in the... 

Metabolism - Fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid. 

Verapamil and its active metabolite norverapamil were assayed from serum (frozen at -18°C) using a gas chromatographic-mass spectrometric method [5]. The detection limit of the method was 1 ng/ml. The areas under the concentration-time curves (AUC 0-32 h) were calculated by the trapezoidal method. Statistical evaluation was carried out using the paired Wilcoxon test and paired Student s t test. 

Ghosh, G.C., Nakada, N., Yamashita, N. and Tanaka, H. (2010) Oseltamivir carboxylate, the active metabolite of oseltamivir phosphate (Tamiflu), detected in sewage discharge and river water in Japan. Environ. Health Perspect., 118 (1), 103-107. 

The pharmacokinetics of enrofloxacin and its active metabolite, ciprofloxacin, have been further extensively studied in sea bass after treatment by oral gavage or water, at a temperature of 15 C (157). Enrofloxacin was absorbed and eliminated slowly after oral administration to the sea bass. Following bath treatment, enrofloxacin efficiently penetrated fish tissues but it was poorly metabolized compared with mammals. On the other hand, ciprofloxacin was generally detected in very low concentrations (less than 0.02 ppm) in plasma samples after both oral and bath treatment. Liver levels of ciprofloxacin were found to be 0.12 ppm after a 5 ppm bathing for 24 h, 0.06 ppm after a 10 ppm bathing for 8 h, and 0.33 ppm after a 50 ppm bathing for 4 h, suggestive of hepatic metabolism of enrofloxacin. 

Pearson, P.G., Omichinski, J.G., Myers, T.G, Soderlund, E.J., Dybing, E. Nelson, S.D. (1990a) Metabolic activation of l,2-dibromo-3-chloropropane to mutagenic metabolites detection and mechanism of formation of (Z)- and ( )-2-chloro-3-(bromomethyl)oxirane. Chem. Res. Toxicol., 3, 458-466... 

Vlase, L., Imre, S., Muntean, D., and Leucuta, S. E. (2007). Determination of loratadine and its active metabolite in human plasma by high-performance liquid chromatography with mass spectrometry detection. J. Pharm. Biomed. Anal. 44 652-657. 

Galanthamine is metabolized in the liver small amounts of the active metabolites epigalan-thamine and galanthaminone can be measured in the plasma. These metabolites are 130-fold less potent than galanthamine. Negligible quantities of these two metabolites can also be detected in urine. Galanthamine is cleared from the body by excretion in the kidneys renal clearance has been estimated at 0.084 1/kg/h. 

A sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS-MS) assay for the simultaneous determination of donepezil (D) and its pharmacologically active metabolite, 6-O-desmethyl donepezil (6-ODD) in human plasma is developed using galantamine as IS [30]. The analytes and IS were extracted from 500 /A aliquots of human plasma via solid-phase extraction (SPE) on Waters Oasis HLB cartridges. Chromatographic separation was achieved in a rim time of 6.0 min on a Waters Novapak Ci8 (150 mm x 3.9 mm, 4 /an) column under isocratic conditions. Detection of analytes and IS was done by tandem mass... 

Tetrahydrocannabinol is metabolized in the liver to form active metabolites which are further metabolized to inactive polar compounds these are excreted in the urine. Some metabolites are excreted into the bile and then recycled via the enterohepatic circulation. Because of their high lipophilicity, most active metabolites are widely distributed in fat deposits and the brain, from which sources they are only slowly eliminated. The half-life of elimination for many of the active metabolites has been calculated to be approximately 30 hours. Accordingly, accumulation occurs with regular, chronic dosing. Traces of the cannabinoids can be detected in the blood and urine of users for many days after the last administration. There is some evidence of metabolic tolerance occurring after chronic use of the drug. THC and related cannabinoids readily penetrate the placental barrier and may possibly detrimentally affect foetal development. 

---