Drug metabolism aliphatic

Aliphatic Oxidation and O-Dealkylation - Cytochrome P-450 monoxygenases appear to be involved in a variety of aliphatic hydroxylations. One common pathway involves an initial w-hydroxylation as with pentobarbital, followed by further metabolism to the aldehyde and acid by dehydrogenases. Hydroxylation also frequently occurs at the penultimate carbon as in amobarbital l, at benzylic and allylic positions and at carbons bearing a heteroatom. Many examples of such oxidations are cited in a recent review.Hydroxylation at carbon bearing a heteroatom such as oxygen, nitrogen or sulfur leads to the so-called dealkylation reactions so common in drug metabolism. 

Vesey et al. 1976) and a series of commercially important, simple, aliphatic nitriles (e.g., acetonitrile, propionitrile, acrylonitrile, n-butyronitrile, maleonitrile, succinonitrile) (Willhite and Smith 1981) release cyanide upon metabolism. These drugs and industrial chemicals have been associated with human exposure to cyanide and have caused serious poisoning and, in some cases, death. 

Oxidation Aliphatic Carbon Atoms. Oxidation at the terminal carbon atom of an alkyl substituent is co-oxidation oxidation of the carbon atom located second from the end is co-1 oxidation. Unless specifically catalyzed by an enzyme, co-1 oxidation tends to occur more frequently. The anticonvulsant drug ethosuximide is metabolized at both the CO and co-1 position. 

In sheep orally dosed with 40 mg/kg bw radiolabeled thiophanate, only the parent drug and its major metabolite lobendazole could be detected in plasma for 65 h after dosing. In sheep liver, thiophanate was metabolized to lobendazole at a rate of approximately 34%. Other metabolites included 2-aminobenzimidaz-ole, low molecular-weight aliphatic acids, and limited amounts of the glucuronide and sulfate conjugates. 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

Hepatic metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including TV-dealkylation and aliphatic hydroxylation. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are pharmacologically active, with long half-lives. 

When taken with meals, a 30% increase in absorption of the drug was observed, with peak plasma concentrations occurring within 2.5-4 h after oral administration. When coadministered with ritonavir, the overall half-life is improved to 15 h.20 Darunavir (1) has been shown to be metabolized by liver enzyme CYP450 (3A4).21 22 Thus when administered with low-dose ritonavir—a CYP450 and protease inhibitor—bioavailability increases from 37% to 84%. Absorption of darunavir occurs primarily in the intestine through passive intracellular diffusion. Darunavir and its metabolites are excreted primarily in the feces and urine.23 Metabolism occurs via, carbamate hydrolysis, aliphatic hydroxylation, aromatic hydroxylation, and other metabolites. 

Ibuprofen, as shown in Scheme 11.8, affords an example of aliphatic hydroxylation. Other drugs similarly metabolized include terfenadine, pentobarbital, and cyclosporine. 

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