O-dealkylation

Elecainide is weU absorbed and 90% of the po dose is bioavailable. Binding to plasma protein is only 40% and peak plasma concentrations are attained in about 1—6 h. Three to five days may be requited to attain steady-state plasma concentrations when multiple doses are used. Therapeutic plasma concentrations are 0.2—1.0 lg/mL. Elecainide has an elimination half-life of 12—27 h, allowing twice a day dosing. The plasma half-life is increased in patients with renal failure or low cardiac outputs. About 70% of the flecainide in plasma is metabolized by the Hver to two principal metaboUtes. The antiarrhythmic potency of the meta-O-dealkylated metaboUte and the meta-O-dealkylated lactam, relative to that of flecainide is 50 and 10%, respectively. The plasma concentrations of the two metaboUtes relative to that of flecainide are 3—25%. Elecainide is mainly excreted by the kidneys, 30% unchanged, the rest as metaboUtes or conjugates about 5% is excreted in the feces (1,2). 

Fenoldopam (76) is an antihypertensive renal vasodilator apparently operating through the dopamine system. It is conceptually similar to trepipam. Fenoldopam is superior to dopamine itself because of its oral activity and selectivity for dopamine D-1 receptors (D-2 receptors are as.sociated with emesis). It is synthesized by reduction of 3,4-dimethoxyphenylacetonitrile (70) to dimethoxyphenethylamine (71). Attack of diis last on 4-methoxystyrene oxide (72) leads to the product of attack on the epoxide on the less hindered side (73). Ring closure with strong acid leads to substituted benzazepine 74. O-Dealkylation is accomplished with boron tribromide and the catechol moiety is oxidized to the ortho-quinone 75. Treatment with 9NHC1 results in conjugate (1,6) chloride addition and the formation of fenoldopam (76) [20,21]. 

Figure 18.2 Representative receiver operator curves to demonstrate the leave n out validation of K-PLS classification models (metabolite formed or not formed) derived with approximately 300 molecules and over 60 descriptors. The diagonal line represents random. The horizontal axis represents the percentage of false positives and the vertical axis the percentage of false negatives in each case. a. Al-dealkylation. b. O-dealkylation. c. Aromatic hydroxylation. d. Aliphatic hydroxylation. e. O-glucuronidation. f. O-sulfation. Data generated in collaboration with Dr. Mark Embrechts (Rensselaer Polytechnic Institute).

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

Smith and Rosazza have suggested that microbial transformation experiments could best be carried out by using a series of perhaps 10 metabolitically prodigious microorganisms as microbial models. Microorganisms for such work may be selected on the basis of considerable literature precedence for their abilities to catalyze the desired biotransformation reaction (i.e., O-dealkylation, N-dealkylation, aromatic hydroxylation, and reductions). The alkaloid substrate... 

Scheme 23. O-Dealkylation reactions of apoiphines by Cunninghamella elegans ATCC 9245.

Octynoic acid, 5 34t Ocular drug delivery, 9 50 Ocular infections, sulfonamides for, 23 499 ODA/PPTA fibers, uses for, 19 734-735 Oddy test, in fine art examination/ conservation, 11 409 O-dealkylation, 9 441 Odometric titration method, 14 59 Odontalag, molecular formula and structure, 5 9 It Odor... 

N-dealkylation, O-dealkylation, oxidative dehalogenation, and oxidation of aryl and alkyl methyl groups. 

The O-dealkylation of ethers, while not as frequently encountered as N-dealkylation in drug metabolism studies, is still a common metabolic pathway. Mechanistically it is less controversial than N-dealkylation in that it is generally believed to proceed by the HAT pathway, i.e., a-hydrogen atom abstraction followed by hydroxyl radical rebound, and not a SET pathway (Fig. 4.58). The product of the reaction is unstable, being a hemiacetal or hemiketal depending on the number of hydrogens on the a-carbon, which dissociates to generate an alcohol and an aldehyde or ketone. 

Halogen dealkylation mimics O-dealkylation both in terms of mechanism and the commonality of the process. Virtually any drug that contains a carbon-hydrogen bond adjacent to a halogen atom will be subject to P450-catalyzed oxidative dehalogenation (Fig. 4.61). 

FIGURE 4.59 Examples (phenacetin, codeine, dextromethorphan, and metoprolol) of cytochrome P450-catalyzed O-dealkylation. 

By analogy to N- and O-dealkylation reactions, one might expect esters and amides to be susceptible to P450-catalyzed oxidative attack at the a-carbon to oxygen (esters) or a to nitrogen (amides). This is indeed the case and was first established (132) by demonstration that the pyridine diester (Fig. 4.66) was oxidatively cleaved by rat-liver microsomes to yield the monoacid as shown. 

FIGURE 4.66 P450-catalyzed oxidative O-dealkylation of an ester. 

A relatively unique type of reactive metabolite is carbene, i.e., a divalent carbon, which is a proposed intermediate in the oxidation of methylene dioxy-containing compounds. A methylenedioxy group in aromatic compounds is subject to O-dealkylation, e.g., 3,4-methylenedioxyamphetamine, as shown in Figure 8.20. The process generates formic acid and the catechol metabolite as final products. However, in the course of the reaction, a... 

FIGURE 8.20 O-dealkylation of a methylenedioxy-containing drug with formation of a carbene-P450 complex. 

Pesticides containing methyl or other alkyl substituents maybe linked to N or 0 (i.e., N- or O-alkyl substitution). An N- or O-dealkylation catalyzed by microorganisms frequently results in loss of the pesticide activity. Phenylurea (see Chap. 1) becomes less active when microorganisms AT-demethylate the molecules (e. g., the conversion of Diuron to the normethyl derivative, Fig. 7). The subsequent removal of the second AT-methyl group renders the molecule fully nontoxic [169]. On the other hand, the microbial O-demethylation of Chloroneb creates the non-toxic product 2,5-dichloro-4-methoxyphenol (Fig. 7). 

From these data, it can be estimated that chlorphenoxamine (11.24, R = 4-C1, R = Me) should hydrolyze ca. 17 times faster than diphenhydramine. This decreased stability appears sufficient to drive formation of detectable amounts of the benzhydrol metabolite (11.25, R = 4-C1, R = Me) in the stomach of patients dosed with chlorphenoxamine. Indeed, ether bond cleavage to form this and derived metabolites was a major pathway in humans [49], Whether the reaction was entirely nonenzymatic or resulted in part from oxidative O-dealkylation (Chapt. 7 in [50]) remains unknown. 

Parmar D, Dhawan A, Seth PK. 1998. Evidence for O-dealkylation of 7-pentoxyresorufin by cytochrome P450 2B1/2B2 isoenzymes in brain. Mol Cell Biochem 189 201-205. 

In a biotransformation system designed to mediate the o-dealkylation of 7-ethoxycumarin to 7-hydroxycoumarin, the genes for the P450 from Streptomyces peucelius and putidaredoxin reductase (CamA) and putidaredoxin (CamB) from... 

Microsomal oxidations may be subdivided into aromatic hydroxylation aliphatic hydroxylation alicyclic hydroxylation heterocyclic hydroxylation N-, S-, and O-dealkylation N-oxidation N-hydroxylation S-oxidation desulfuration deamination and dehalogenation. 

O-dealkylation. Aromatic methyl and ethyl ethers may be metabolized to give the phenol and corresponding aldehyde (Fig. 4.16), as illustrated by the de-ethylation of phenacetin (Fig. 4.20). Ethers with longer alkyl chains are less readily O-dealkylated, the preferred route being co-l-hydroxylation. 

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