CYP-dependent metabolism

Atorvastatin, simvastatin, rosuvastatin Inhibit HMG-CoA reductase Reduce cholesterol synthesis and up-regulate low-density lipoprotein (LDL) receptors on hepatocytes modest reduction in triglycerides Atherosclerotic vascular disease (primary and secondary prevention) t acute coronary syndromes Oral duration 12-24 h Toxicity Myopathy, hepatic dysfunction Interactions CYP-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors... 

Abbreviations f, fraction of the dose metabolized by all CYPs , P45o, fraction of total CYP-dependent metabolism catalyzed by each CYP / xfnj 450, contribution of a specific CYP enzyme to overall clearance. 

FIGURE 5.4 Proposed clinical drug interaction studies based on in vitro CYP reaction phenotyping data. It is assumed that the drug in question is cleared via CYP-dependent metabolism (/m LO)-... 

The nasal route of drug delivery avoids the liver first-pass effect, but the pseudo-first-pass effect owing to nasal metabolism of drugs is still a concern. Many enzymes such as carboxylesterase, aldehyde dehydrogenase, glutathione transferases, UDP-glucoronyl transferase, epoxide hydrolases, CYP-dependent monoxygenases, exo- and endopeptidases and proteases are present in the nasal mucosa.106 108,110,116 CYP enzymes are present abundantly in the olfactory epithelium.107,110... 

Acetylation is a very common metabolic reaction, which occurs with amino, hydroxyl or sulfhydryl groups. The acetyl group is transferred from acetyl-Coenzyme A, and the reaction is catalyzed by acetyltransferases. An important aspect of this kind of substitution is the genetic polymorphism of one acetyltrans-ferase in humans, who are divided into fast and slow acetyla-tors. In a few cases, the conjugates are further metabolized to toxic compounds, as is seen with isoniazid. Some evidence exists that acetylation of the antitubercular isoniazid leads to enhanced hepatotoxicity of the drug. " Acetylation followed by hydrolysis and CYP-dependent oxidation yields free acetyl... 

Figure 19.9 Metabolic possibilities for model compounds having representative functionality. Selected phase 1 reactions (1) Hydrolysis of various types of esters, in this case mediated by a carboxylesterase (2) N-dealkylation mediated by certain of the Cytochrome P-450 (CYP) enzymes (3) O-dealkylation mediated by certain of the CYPs and (4) Aromatic hydroxylation also mediated by certain of the CYPs. Depending upon the subtleties of their electronic and steric environments, the relative competitive biotransformation rates for these processes will generally be (1) (2) > (3) (4). Selected phase 2 reactions (5) Formation of a glucuronic acid conjugate (or in some cases a sulfate conjugate) and (6) N-acetylation. In terms of relative biotransformation rates in general (5) >> (6).

Because of the experimental manifestation of time-dependency and requirement for CYP catalysis, mechanism-based CYP inactivation is often referred to as time-dependent, metabolism-dependent, or preincubation-dependent inhibition. A detailed description of the kinetic characteristics of this type of inhibition has been published (Silverman, 1988) and a simplified kinetic equation is presented in Table 5.1. In cases where CYP activity can be recovered by dialysis, the term quasi-irreversible inhibition has been proposed (Ma et al., 2000). In addition, a time-dependency of CYP inhibition can result from the formation of potent yet reversible metabolites (Ma et al., 2000 Zhao et al., 2002 Zhout et al., 2005). Formation of a metabolite-intermediate (MI) complex has been described as another cause for time-dependent CYP inhibition by many quasi-irreversible inhibitors in this situation the metabolite or intermediate coordinates with the heme-ion thus decreasing the rate of catalysis. 

Hepatocytes, whether freshly cultured or cryo-preserved, can provide an assessment of not only CYP metabolism but also clearance by other metabolizing enzymes and potentially the role of transporters [51]. The accuracy of the data is of course dependent on how well the proteins in the hepatocytes function after culturing or freezing. 

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