Pharmacologically active metabolites

Imipramine is demethylated to desipramine, and amitriptyline is demethylated to nortriptyline. Both 

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Graham, G.G., Whitehouse, M.W. and Bushell, G.R. (2008) Aurocyanide, dicyano-aurate (1), a pharmacologically active metabolite of medicinal gold complexes. Inflammopharmacology, 16, 126-123. 

Pai HV, Upadhya SC, Chinta SJ, Hegde SN, Ravindranath V. 2002. Differential metabolism of alprazolam by liver and brain cytochrome (P4503A) to pharmacologically active metabolite. Pharmacogenomics J 2 243-258. 

Oral absorption of carbamazepine is quite slow and often erratic. Its half-life is reported to vary from 12 to 60 hours in humans. The development of blood level assays has markedly improved the success of therapy with this drug, since serum concentration is only partially dose related. Carbamazepine is metabolized in the liver, and there is evidence that its continued administration leads to hepatic enzyme induction. Carbamazepine-10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own. 

It is highly protein bound and is metabolized to pharmacologically active metabolite. It crosses placental barrier. 

It is a pharmacologically active metabolite of terfenadine, is a non sedating antihistaminic with selective peripheral receptor antagonist activity. 

Those biotransformed by oxidative metabolism in the liver, primarily Ai-demethylation or hydroxylation (e.g., adinazolam, chlordiazepoxide, clobazam, diazepam, flunitrazepam, and medazepam), often yield pharmacologically active metabolites that must undergo further metabolic steps before excretion. 

The biotransformation of the phenylpiperidines is primarily by hepatic phase I metabolism, catalysed by cytochrome P-450 isoenzymes. The elimination of alfentanil is significantly slowed in patients treated with erythromycin, a P-450 inhibitor, with delayed recovery and prolonged postoperative respiratory depression (Bartkowski and McDonnell 1990). Apart from pethidine and phenoperidine, none of the phenylpiperidines has pharmacologically active metabolites. 

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... 

These drugs include alcohols (ethchlorvynol, chloral hydrate), piperidinediones (glutethimide, methyprylon), and carbamates (meprobamate). They are rarely used in therapy, though the low cost of chloral hydrate makes it attractive for institutional use. Little is known about their molecular mechanisms of action. Most of these drugs are biotransformed to more water-soluble compounds by hepatic enzymes. Trichloroethanol is the pharmacologically active metabolite of chloral hydrate and has a half-life of 6-10 hours. However, its toxic metabolite, trichloroacetic acid, is cleared very slowly and can accumulate with the nightly administration of chloral hydrate. 

Some anticonvulsants are metabolized in the liver to pharmacologically active metabolites which, if they have long half-lives, may accumulate and have neurotoxic effects. The following commonly used anticonvulsants are known to produce active metabolites ... 

Furlong MT et al (2012) A validated LC-MS/MS assay for the simultaneous determination of the anti-leukemic agent dasatinib and two pharmacologically active metabolites in human plasma application to a clinical pharmacokinetic study. J Pharm Biomed Anal 58 ... 

EME and BEG, which is mainly obtained by enzymatic hydrolysis, represents respectively the 32-49 % and 29 45 % of total urinary metabolites cocaine can be converted, in small amounts, to norcocaine (NCOC) and psychoactive metabolite norbenzoylecgonine (NBE). The combined intake of alcohol and cocaine determines the formation of a pharmacologically active metabolite, the cocaethylene (ethyl ester of benzoylecgonine, CE), with a significant liver toxicity [13],... 

This assay is used for the quantitative determination of the angeotensin converting enzyme (ACE) inhibitor ramipril, (2-[N-[(S)-l-Ethoxycarbon-yl-3-phenylpropyl]-L-alanyl]-(lS,3S,5S)-2-azabicy-clo[3.3.0]octane-3-carboxylic acid), and its pharmacologically active metabolite, ramiprilat, in human urine using capillary gas chromatography with nitrogen specific detection (NPD). 

This assay is used for the quantitative determination of benazepril and its active metabolite, benazeprilat, in human plasma by capillary gas chromatography-mass selective detection (Pommier et al. 2003). Benazepril hydrochloride, 3- [l-ethoxycarbonyl-3-phenyl-(lS)-propyl]amino -2,3,4,5-tetrahydro-2-oxo-l-(3S)-benzazepine-l-acetic acid hydrochloride, is a prodrug-type angiotensin-converting enzyme (ACE) inhibitor which, on absorption, is hydrolysed to a pharmacologically active metabolite, the dicarboxylic acid (benazeprilat). 

Knowledge about metabolites and their activity is further an important criteria for the assessment of species-specific effects and differences, e.g. the search for the most human-like test model as the best predictor for human reactions, focuses on such differences. Metabolism can lead to pharmacologically active metabolites such knowledge is desirable early in development. In vitro metabolism studies normally precede in vivo preclinical safety assessments. 

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