Enzyme/transporter inhibitor

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

For compounds not metabolized by the gut wall, liver, or affected by transporters, a direct relationship between oral absorption and bioavailability should be observed. The calculated oral absorption, using PSA as a measure for passive membrane permeability reflecting the absorption step, relates to the in vivo observed bioavailability for three classes of compounds - angiotensin-converting enzymes (ACE) inhibitors, P-blockers, and calcium antagonists - is shown below [25],... 

Like conventional enzymes, transport proteins often are sensitive to specific inhibitors. For example, the anion transporter of the erythrocyte plasma membrane, which moves HC03- and Cl- ions across the membrane, is inhibited by 1,2-cyclohexadione or derivatives of stilbenedisul-fonate. Because these inhibitors react covalently with amino acid residues of the protein, they afford useful probes for the location and structure of the anion-binding site. 

Each term with a metabolic component (Fgm, Fh, CL) is a function of unbound fraction in blood (/ ) and intrinsic clearance (i.e., Emax/Km in biochemical terms) and can be modified by an enzyme/transporter inducer or inhibitor. If chug is completely absorbed and elimination occurs exclusively in the liver, the systemic AUC observed in the presence of a metabolic modulator would directly reflect... 

Intestinal absorption of beta-lactams occurs at least in part by an active mechanism involving a dipeptide carrier, and this pathway can result in interactions with dipeptides and tripeptides (196,197), which reduce the rate of absorption of the beta-lactams. In particular, angiotensin-converting enzyme (ACE) inhibitors, which have an oligopeptide structure, are absorbed by the same carrier (198) and interact with beta-lactams in isolated rat intestine (199). However, there might be a second site of interaction between ACE inhibitors and beta-lactams. Both groups of substances are excreted by the renal anionic transport system, and concomitant administration of both drugs sometimes results in pronounced inhibition of the elimination of beta-lactams (200). In the case of cefalexin, it may not lead to toxic effects. However, when more toxic beta-lactams are used, the possibility of this interaction has to be kept in mind. 

In recent years, there has been increasing awareness regarding the importance of transporters in the absorption and disposition of NMEs. While the major portion of NMEs or marketed drugs traverse cell membranes by passive diffusion, there are numerous examples where the involvement of specialized transport mechanisms has been demonstrated. Examples include the role of oligopeptide transporters in the intestinal absorption of P-lactam antibiotics, angiotensinconverting enzyme (ACE) inhibitors, and novel NMEs as well as the role of P-glycoprotein (P-gp) in the secretion of molecules into the intestine [11,77—79]. Transfection of cells with the transporter protein of interest has permitted the evaluation of precise cellular mechanisms of uptake and transport of NMEs. Transfected cell lines by definition are tailor-made to overexpress the protein of... 

Zymogen (e.g., trypsinogen and chymotrypsinogen) synthesis, secretion, transport, and activation and the rate of inactivation of the active enzyme by inhibitors may all be considered means of enzyme regulation. 

Table 1. Some cytochrome P450 3A4 enzyme and P-glycoprotein efflux transporter inhibitors, inducers, and shared substrates with nephrotoxic potential. Inhibitors Inducers Substrates Erythromycin Amiodarine Cyclosporine ...

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