N-deethylation

N-demethylation at the three N-methyl sites. In this regard, the 3-N-demethylation of caffeine to generate paraxanthine can serve as a particularly good in vivo indicator of the presence and activity of CYP1A2 (Fig. 4.7). In the case of phenacetin, CYP1A2 catalyzes N-deethylation to generate acetaminophen. Not unexpectedly, 1 A2 s selectivity toward heterocyclic aromatic substrates carries over to inhibitors of the enzyme. Furafylline (Fig. 4.7) is an example of a particularly potent 1A2 mechanism-based inhibitor. 

Reaction of 4,6-diethoxy-l-ethylpyrimidinium tetrafluoroborate (21) showed similar behavior no N-deethylation, but deethoxylation at position 4 as well as at position 6 was observed, as indicated by the formation of the two isomeric products l,4-dihydro-6-ethoxy-l-ethyl-4-iminopyrimidine hydrogen tetrafluoroborate (23) and l,6-dihydro-4-ethoxy-l-ethyl-6-... 

Aconitum yesoense var. macroyesoense (Nakai) Tamura 12-0- Acetyl-1,19-dehydrolucidusculine 1 -O-Acety Uuciculine 12-0- Acety llucidusculine 15-Benzoy lpseudokobusine N-Deethyl-1,19-dehydrolucidusculine... 

Ohyama K, Nakajima M, Suzuki M, et al. Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities prediction of in vivo drug interactions. Br J Clin Pharmacol 2000 49 244—253. 

Some insecticides are known to affect the process of oxidative phosphorylation (Figure 7.27). Sulfluramid is first N-deethylated by cytochrome P450 monooxygenases to become perfluorooctane sulfonamide in vivo (Figure 7.28). This oxidative metabolite acts... 

Fabre G, Julian B, Saint-Aubert B, Joyeux H, Berger Y. Evidence for CYP3A-mediated N-deethylation of amiodarone in human liver microsomal fractions. Drug Metab Dispos 1993 21(6) 978-85. 

Olofson and coworkers also introduced vinyl chloroformate as a reagent for the N-dealkylation of tertiary amines (Ref. 157,158,159). Compared with commonly utilized reagents in N-dealkylation procedures, the use of VOC-CI leads to significantly improved yields under milder conditions combined with greater discrimination between alkyl groups in unsymmetrical amines. The procedure is illustrated by the selective N-deethylation of N-ethyl piperidine to afford piperidine.HCI in 90% yield (Ref. 159) as depicted in scheme 107. 

Scheme 107 N-Deethylation ofNethyl piperidine with vinyi chioroformate.

Thus, in the initial test system (N-deethylation of N-ethylpiperidine), the use of a-chloroethyl chloroformate (acronym ACE-CI) surpassed the yield obtained with vinyl chloroformate (I) -> (IV), 99% w 90% as shown in scheme 132 (Ref. 189). 

Enrofloxacin is mainly eliminated by hepatic metabolism, and systemic clearance of the drug varies between species. In sheep, horses, dogs and pigs the average clearance of enrofloxacin is in the range 5.75-8.56 mL/min kg, while enrofloxacin clearance (mL/min kg) differs more widely between other species rabbits (17.9), llamas (12.0), chickens (3.3), turkeys (8.9), houbara bustard (5.7) and fingerling rainbow trout (Oncorhynchus mykiss) at 15°C (1.25). Systemic clearance of enrofloxacin represents mainly hepatic clearance composed of a variety of metabolic pathways, which include N-deethylation to ciprofloxacin. 

A recent study has employed deuterium labeling to show that the mechanism for the oxidative N-demethylation of nicotine may involve two modes of breakdown for a proposed carbinolamine intermediate, dealkylation with formaldehyde formation and dehydration to an iminium ion.72 The formation of such an sp2-hybrid intermediate may help to explain why both a primary and substantial / -secondary deuterium isotope effect were observed for the N-deethylation of the antiarrhythmic agent, lidocaine.73 In contrast, only a primary isotope effect was observed on the rate of oxidative O-deethylation of deuterated analogs of the analgesic, phenacetin. 77 These results indicate differences in the mechanism of oxidative 0- and N-dealkylation. A final example of the use of secondary deuterium isotope effects in studying enzymes involved in drug metabolism revealed an SN-2-like transition state for the transfer of a methyl group catalyzed by catechol-O-methyl transferase.73... 

Benzphetamine is a methamphetamine whose tertiary amine also carries a benzyl group. The likelihood of metabolic N-debenzylation yielding methamphetamine would, of course, explain its effects. Diethylpropion (No. 14) is an interesting compound because of its particularly involved metabolic degradation, which is initiated by stepwise N-deethylation and keto reduction to a P-OH. These active metabolites, presumably with the parent compound, explain both anorexiant and CNS effects, as well as the reduced level of the latter when compared with amphetamine. Subsequent oxidations all the way to benzoic, hydrox-ybenzoic, and mandelic acids all lead to inactivation. 

The N-deethylated metabolite, although still bioactive, is then rapidly cleaved by microsomal amidases to inactive m-xylidine and N-ethylglycine. This readily explains the short half-life of the drug. 

The half-life of ethirimol in plants is longer about 3-4 days. The first step in decomposition is the N-deethylation of ethirimol and the formation of the inactive 2-amino derivative. In addition, both active substances are converted into water-soluble metabolites, some of which are also fungitoxic. It has been established that these metabolites are conjugates with glucosides or phosphates (18). Small quantities of hydroxybutyl derivatives (19) have also been detected. 

Of the eight or more products metabolised with liver homogenates N-deethyl benthiocarb, bis(4-chlorobenzyl) mono- and disulfides and 4-chlorobenzoic acid could be identified. 

The inhibitory activity of PED appears to be specific for aromatase. This steroid did not affect the activity of cytochrome P450-mediated ethylmorphine N-deethylation, nor did it prolong the pentobarbital sleeping time in rats in vivo, used as an index for in vivo cytochrome P450 activity Moreover, PED was endocrinologically inactive and had very... 

Major metabolites Oxidation to carboxylic acids N-deethylation N-desmethyl Oxid alcohol... 

Lidocaine, similar to procaine, is an effective, clinically used local anesthetic (Fig. 26.11) (see Chapter 16). Its cardiac effects, however, are distinctly different from those of procainamide or quinidine. Lidocaine normally is reserved for the treatment of ventricular arrhythmias and, in fact, usually is the drug of choice for emergency treatment of ventricular arrhythmias. Its utility in these situations results from the rapid onset of antiarrhythmic effects on intravenous infusion. In addition, these effects cease soon after the infusion is terminated. Thus, lidocaine therapy may be rapidly modified in response to changes in the patient s status. Lidocaine is effective as an antiarrhythmic only when given parenterally, and the intravenous route is the most common. Antiarrhythmic activity is not observed after oral administration because of the rapid and efficient first-pass metabolism by the liver. Parenterally administered lidocaine is approximately 60 to 70% plasma protein bound. Flepatic metabolism is rapid (plasma half-life, -15-30 minutes) and primarily involves N-deethylation to yield monoethylglycinexylide, followed by amidase-catalyzed hydrolysis into N-ethylglycine and 2,6-dimethylaniline (2,6-xylidine) (Fig. 26.12). 

N-deacetylisoipecoside, 117-118 N-deethyl-3-acetylaconitine, 56-57 N-deethyldeoxyaconitine, 56-57 / -d ethylarwedine, 118 A -demethylgalanthamine, 41, 4U, 118 -d ethylnarwedine, 118 -d ethylpuqietinone, 58-59 A -desmethyl-8a-e1hoxypretazettine, 206-207... 

Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, Yokoi T (2000) A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation an approach to predict the contribution... 

Hanioka N, Matsumoto K, Saito Y, Narimatsu S (2011) Influence of CYP2C8 13 and CYP2C8 14 alleles on amiodarone N-deethylation. Basic Clin Pharmacol Toxicol 108 359 362... 

Soyama A, Hanioka N, Saito Y, Murayama N, Ando M, Ozawa S, Sawada J (2002) Amiodarone N-deethylation by CYP2C8 and its variants, CY-... 

Wang JS, Backman JT, Taavitsainen P, Neuvonen PJ, Kivisto KT. Involvement of CYPl A2 and CYP3A4 in Udocaine N-deethylation and 3-hydroxylation in humans. DrugMetab Dispos 2000 28(8) 959-695. 

In urine - 8 metabolites. Gluc.(H) oxolinic acid complex (unidentified) (m) N-deethylation. Active metabo-lites in urine, feces. Other metabolites, unidentified glue, and non glue. 

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