Phase I Biotransformations

TABLE 18.5. Summary of Prominent Phase I Biotransformation Reactions... 

The answer is b. (Hardman, p 906.) Cimetidine reversibly inhibits cytochrome P450. This is important in phase I biotransformation reactions and inhibits the metabolism of such drugs as warfarin, phenytoin, propranolol, metoprolol, quinidine, and theophylline. None of the other enzymes are significantly affected. 

Cytochrome P450 1A content CYPIA Phase I biotransformation enzyme PAHs, PCBs, PCDDs, PCDFs Liver tissue 6-15... 

In a recent version of the program the likelihood of many Phase I biotransformations is reduced after the first generation. This action reflects the lower probability of second and subsequent generation metabolites being produced in significant quantities. The assigned likelihoods are... 

With regard to drug interactions, it is important to note that the cytochrome P-450 system is not involved in the metabolism of moxifloxacin. In vitro studies using cytochrome P-450 enzymes have shown that moxifloxacin does not inhibit the enzymes CYP 1A2, CYP 3A4, CYP 2C9, CYP 2C19, and CYP 2D6. Moxifloxa-cin s metabolic profile makes it highly unlikely that it will alter the pharmocoki-netics of drugs affected by these enzymes. In rhesus monkeys, oxidative phase I biotransformations do play an additional role, however [272,273]. 

The second type of conjugation reaction involves the coupling of the endogenous conjugating ligand with a high-energy or reactive xenobiotic. The reactivity associated with the xenobiotic is sometimes the consequence of Phase I biotransformation (e.g., epoxidation, Chapter 10). 

The electrophilic center may already be present in the compound, or it may arise as a consequence of Phase I biotransformation, as in epoxides. Conjugations with GSH may be classified broadly as replacement [substitution Eq. (27)] or addition [Eq. (28) R = electron-withdrawing group] reactions. With the latter type in particular, new asymmetric centers are created, but only... 

Demethylation by phase I biotransformation is the major pathway, with 6-chloronicotinic acid being the major metabolite. Compounds can then undergo phase II transformation with glycine conjugation representing the major pathway. 

PAHS are readily absorbed via the gastrointestinal tract and then metabolically transformed to more reactive forms. These toxicants are typically converted into more reactive metabolites through phase I biotransformations, and then converted into more readily excretable conjugates via phase II processes. 

Microsomal oxidative reactions constitute the most prominent phase I biotransformation pathway for a wide variety of structurally unrelated drugs (Table 1.4). Some drugs (e.g. amphetamine, diazepam, propranolol, lignocaine) simultaneously undergo more than one type of microsomal-mediated oxidative reaction. Microsomal enzymes are located primarily in liver cells, where they are associated with the smooth-surface (without ribosomes) endoplasmic reticulum (Fouts, 1961). Lipid solubility is a prerequisite for drug access to the... 

Phase I biotransformation reactions usually convert the parent drug to a... 

Table 1.5 Some pharmacological agents that are converted by phase I biotransformation reactions to active metabolites.

In phase I biotransformations the parent chug molecule is enzymatically converted to a polar metabolite by the conjugation of a functional group to the drug molecule (or removal of a functional group, depending on the structure), making the molecule more polar in character. If the metabolite produced is not readily excreted, a subsequent phase II reaction occurs. 

Biotransformation is the metabolic conversion of drugs, generally to less active compounds but sometimes to iso-active or more active forms. Phase I biotransformation occurs via oxidation, reduction, or hydrolysis. Phase II metabolism occurs via conjugation. 

Six phase I metabolites were identified by analysing the spectral data alongside an expert chemist s review of the public literature. Meteor (version 7) predicted five of the six metabolites, along with products arising from sulfonation, glucuronidation, hydrolysis and other pathways. Meteor did not predict M3 (Figure 11.11), which is thought to arise from the sequential application of two phase I biotransformations on the parent V-dealkylation and benzylic hydroxylation. Biotransformation likelihood can be attenuated by consideration of whether the process is the first step in a sequence or a subsequent step. On this occasion, the likelihood of the second phase I process... 

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