Biotransformation pathways metabolites

Other chlorotriazines (simazine, propazine, terbuthylazine) follow the same biotransformation pathway of atrazine therefore, urinary excretion of bi-dealkylated, deisopropylated, and deethylated metabolites is not compound specific. When simultaneous exposure to different chlorotriazines occurs, the unmodified compound measured in urine, even though it represents a minor portion of the absorbed dose, may be useful for a qualitative confirmation of exposure. 

Bromocriptine is rapidly and completely metabolised in animals and man. The major components of the urinary metabolites have been identified as 2-bromo-lysergic acid and 2-bro-mo-isolysergic acid. Apart from the hydrolytic cleavage of the amine bond and the isomerization at position 8 of the lysergic acid moiety, a third principal biotransformation pathway consists in the oxidative attack of the molecule at the proline fragment of the peptide part, predominantly at position 8, giving rise to the formation of a number of hydroxylated and further oxidized derivatives of bromocriptine, and in addition of conjugated derivatives thereof. 

Valuable metabolic insights have been gained from in-depth studies of phenytoin (diphenylhydantoin, 10.21), whose main biotransformation pathway is by cytochrome P450 catalyzed phenyl oxidation. Incubations with rat liver 9000 g supernatant produced the para-phenol (4 -hydroxyphenytoin) as the major metabolite, and the dihydrodiol in smaller proportions. Minute amounts of other metabolites were also detected, e.g., the meto-phenol and the 3-O-mclhylcalcchol. Studies in rats confirmed the urinary excretion, in decreasing order of importance, of the para-phenol, the dihydrodiol, and the 3-O-mclhylcalcchol metabolites [78][79],... 

Depending on the species, parbendazole, mebendazole, albendazole, oxfendazole, cambendazole, and febantel can be teratogenic in the parent form or indirectly from metabolite formation. Oxibendazole and fenbendazole in parent form are not teratogenic, although one of the metabolites of fenbendazole, a sulfoxide found in the milk of cows treated with fenbendazole, is teratogenic in the rat and sheep. Albendazole displays similar biotransformation pathways in cattle as it does in sheep, yet the bovine animal is refractory to its teratogenic effect at normal dosage rates. 

The metabolite peaks at 30.0 and 28.6 min (Fig. 6.4) are two muraglitazar metabolites resulting from the opening of the oxazole ring (Zhang et al., 2003b). Both metabolites are unusual not only in their biotransformation pathways but also in... 

Superior sensitivity, efficiency, and specificity have made high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS), the predominant analytical technique for characterization and quantitative analysis of metabolites (Kostiainen et al., 2003 Ma et al., 2006 Prakash et al., 2007). Ion trap, triple-quadrupole, and quadmpole time-of-flight (Q-TOF) mass spectrometers are routinely used to profile and characterize metabolites in plasma and excreta (Ma et al., 2006). The combination of scan types and features available on mass spectrometers of different design (product ion, MS", neutral loss, precursor ion scans, accurate mass measurements) allows identification and characterization of putative and unexpected metabolites with or without little prior knowledge of biotransformation pathways of a given dmg molecule. 

Cyclosporin A is slowly but extensively metabolized. The biotransformation pathway and the pattern of the generated metabolites are similar in humans and animals. Approximately 17 single metabolites have been detected so far, all of which are present in considerably lower plasma concentration than cyclosporin A itself [46]. Eleven ether-extractable compounds have been isolated from urine of dog and man and from rat bile and faeces using preparative HPLC and thin-layer chromatography [43]. Structural assignments for these... 

Metabolite identification is central to many of the activities in preclinical development. A more complete characterization of pharmacokinetic properties is performed in animals (typically rats and dogs) during this stage. The knowledge of the biotransformation pathways of the lead candidate to its metabolites is used to indicate the magnitude and duration of activity. Metabolite identification is critical to many of these activities and plays an important role in establishing the dose and toxicity levels. 

During the course of clinical development, it is often important to identify the structures of metabolites. This information provides an opportunity to better understand interpatient variability in pharmacokinetics and toxicity. Clinical studies performed by Lokiec and coworkers, 1996 on a semisynthetic derivative of 20(S)-camptothecin, CPT-11, demonstrate the use of LC/MS to investigate the in vivo metabolic pathways. CPT-11 is a potent inhibitor of topoisomerase II, which is an enzyme involved in DNA duplication, and exhibits significant activity against various types of tumors in clinical studies. The understanding and control of the main biotransformation pathways are particularly important for anticancer drugs because therapeutic doses are often close to the maximum tolerated dose. 

Kassahun K, Pearson PG, Tang W, et al. Studies on the metabolism of troglitazone to reactive metabolites in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidine ring scission. Chem Res Toxicol 2001 14 62-70. 

Most drugs are not excreted unchanged by the kidneys but first are biotransformed to metabolites that then are excreted. Renal failure not only may retard the excretion of these metabolites, which in some cases have important pharmacologic activity, but, in some cases, alters the nonrenal as well as the renal metabolic clearance of drugs (15, 24). The impact of impaired renal function on drug metabolism is dependent on the metabolic pathway, as indicated in Table 5.2. In most... 

Metabolites derived by loss of an alkyl or arylalkyl group from ethers [Eq. (4)], thioethers [Eq. (5)], amines [Eq. (6)], and amides [Eq. (7)] represent common biotransformation pathways (R, R" = H, alkyl or aryl). These processes involve oxidation on carbon adjacent to the heteroatom. The intermediates are generally unstable and readily decompose to the corresponding alcohol, thiol, amine, or amide and an aldehyde. Intermediates formed from amides [Eq. (7)] are more stable and may be detected as excreted metabolites. If a secondary carbon atom is adjacent to the heteroatom, then this portion of the molecule is released as a ketone. The heteroatom may also be located in a cyclic structure (e.g., morpholine, piperazine). Two processes have been adopted for amines, namely, N-dealkylation or deamination, that are essentially the same event. In general, which of the two terms applies depends on the... 

Investigations of biotransformation pathways in vivo require the collection and analysis of appropriate biologic samples. The types of sample collected include urine, feces, expired air, blood and/or plasma, bile, milk, saliva, synovial fluid, and tissues. These samples can be divided into two groups 1) those requiring complete collection (e.g., urine and feces) in order to provide quantitative as well as qualitative information on the excretion of the drug and its metabolites and 2) those such as blood and milk that are subsampled at specific times to yield information on the identity and time-related concentrations of the drug and its metabolites that contribute to systemic exposure. Samples of the above types can be obtained from all the common laboratory animals used in biomedical research. In addition, with the exception of bile and tissues, similar samples can usually be obtained from humans without great difficulty. 

In primary aliphatic amines, such as phentermine. chlorphentcrmine (yx-chlotphentcrmine).- and amantadine. N-oxidation appears to be the major biotransformation pathway because a-carbon hydroxylation cannot occur. In hum-ans. chlorphentcrmine is N-hydroxylated extensively. About 30% of a dose of chlorphentermine is found in the urine (48 hours) as Al-hydroxychlorphentermine (free and conjugated) and an additional 18% as other products of N-oxidation (presumably the nitroso and nitro metabolites). In general, /V-hydroxylamines are chemically unstable and susceptible to spontaneous or enzymatic oxidation to the nitro.so and nitro derivatives. For example, the N-hydroxyl-amine metabolite of phentermine undergoes further oxiila-... 

Hydrolysis is a major biotransformation pathway for drugs containing an ester functionality. This is because of the relative case of hydrolyzing the ester linkage. A classic example of ester hydrolysis is the metabolic conversion of aspirin (acetylsalicylic acid) to salicylic acid. " Of the two aslcr moieties present in cocaine, it appears that, in general, the methyl group is hydrolyzed preferentially to yield ben-roylecgoninc os the major human urinary metabolite. The... 

The major urinary metabolite of cyanamide is n-ace-tylcyanamide. In vitro studies suggest that cyanamide is metabolized to cyanide however, results in vivo suggest this biotransformation pathway is irrelevant in humans. Rapid absorption is anticipated, though bioavailability is incomplete with estimates ranging from 53% to 70%. The estimated half-life in humans after oral administration is expected to be less than 2 h. 

The presence of active metabolites contributes heavily to the duration of action of benzodiazepines. Some active metabolites have much longer plasma half-lives than their parent compounds. If the parent drug is not biotransformed into active metabolites, the duration of action is determined by the rate of elimination of the parent compound. The biotransformation pathways of several benzodiazepines are shown in Figs. 5.4, 5.5, 5.6, and 5.7. 

Ethotoin. Chemically, 3-ethyl-5-phenylhy-dantoin, ethotoin (Ic) undergoes two biotransformation pathways leading to inactive products p-hydroxylation [pathway (1)] and deethylation [pathway (2)]. This product has relatively low potency compared to that of phenytoin. Like phenytoin, ethotoin displays saturable metabolism with respect to the formation of the two metabolites (18). 

Fig. 2. Synthetic scheme of the biotransformation pathways of alkylphenols in fish, based on the references detailed in the main text. Metabolites II to XV have been solely (or predominantly) identified as glucuronic acid conjugates, as displayed for structure I.

Fish have active Phase I and Phase II biotransformation pathways that can modify the disposition and toxicity of pesticides. Although more studies are characterizing in vivo metabolites of pesticides in fish, there is still a significant lack of knowledge about the ultimate fate of these compounds in the fish. In addition, very little is known about the specific enzymes responsible for the formation of specific metabolites of various pesticides. For example, although multiple CYP isoforms have been identified in fish, the substrate specificities with regard to pesticides are unknown and deserve further study. 

Novel Biotransformation Pathways - The recent literature contains examples of some of the newly discovered pathways in addition to those covered in the excellent review by Jenner and Testa.Formation of an aliphatic 0-methyl metabolite (26) of the antiinflammatory agent cicloprofen (27) in the rat, has been demonstrated,and it was proposed that it formed via 0-raethylation of a dihydroxy intermediate (28). Thiomethyl metabolites of phenacetin and acetaminophen have been found in dogs and man. An S-methyl metabolite (29) of bromazepam (50), a minor tranquilizer, in the rat was shown to be formed vitro by biotransformation of a mecapturic acid conjugate (31). 

---