By O. Fasim. Limestone College.
Structure-function analysis of human cytochrome P-4502B6 using a novel substrate buy cheap dapoxetine 90mg erectile dysfunction girlfriend, site-directed mutagenesis discount dapoxetine 30 mg fast delivery erectile dysfunction pump, and molecular modeling. Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations. Direct interaction between substrates and endogenous steroids in the active site may change the activity of cytochrome P450 3A4. Structure-function relationships of human aromatase cytochrome P-450 using molecular modeling and site-directed mutagenesis. Construction of a model of the Candida albicans lanosterol 14-alpha-demethylase active site using the homology modelling technique. Membrane-protein interactions contribute to efficient 27-hydroxylation of cholesterol by mitochondrial cytochrome P450 27A1. X-ray structure of nitric oxide reductase (cytochrome P450nor) at atomic resolution. Improvements in protein secondary structure prediction by an enhanced neural network. A new method for building protein conformations from sequence alignments with homologues of known structure. Deviations from standard atomic volumes as a quality measure for protein crystal structures. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. A general and fast scoring function for protein-ligand interactions: a simplified potential approach. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. Background The gastrointestinal mucosa represents a major physical and metabolic barrier to the systemic availability of orally ingested drug molecules. A critical component of that barrier is a collection of drug-metabolizing enzymes localized primarily at the apical aspect of the intestinal epithelium. The liver is generally considered to be the dominant site of drug metabolism, but it is now clear that for a number of drug molecules (e. Indeed, some prodrugs have been developed that take advantage of the enzy- matic activity of the intestinal mucosa (e. It has also been suggested that a functional interaction occurs between P-gp and meta- bolic enzymes at the apical interface of the mucosa that increases the resi- dence time of a drug molecule and results in enhanced first-pass metabolism at the intestine. It stands to reason that modulation of intestinal drug-metabolizing enzyme and efflux transporter function could constitute a mechanism of drug-drug interaction. In this chapter, we review the expression and localization of intes- tinal enzymes and transporters that have been implicated in metabolically based drug-drug interactions and the pharmacokinetic characteristics of those interaction events. Pharmacokinetic Principles If a metabolically based drug-drug interaction is to have clinical significance, the affected process of drug metabolism must represent an appreciable part of the overall drug elimination scheme. In the case of intestinal metabolism, it is the fraction of a dose metabolized by the gut mucosa on first pass (Egm) that is most relevant. In general, intestinal mucosal enzymes that contribute significantly to the first-pass metabolism of a drug have a much lower contribution to the sys- temic clearance of the same molecule because of the relatively low blood flow to enterocytes that express drug-metabolizing enzymes (1,2). Thus, important drug interactions involving gut metabolism will generally be associated with drugs that have an appreciable first-pass intestinal extraction. In the context of first-pass metabolism after oral administration, it is important to define in what region of the gastro- intestinal tract the majority of the drug dose will be absorbed when assigning 474 Thummel et al.
One major advantage this technique has over an in vivo experiment involves the perfusion fluid used in the experiment dapoxetine 90 mg with amex impotence in men. The composition of the solution can be controlled with respect to test compounds order 60mg dapoxetine overnight delivery erectile dysfunction caused by hemorrhoids, plasma proteins, nutrients, and met- abolic cofactors (432). However, the use of a perfusate solution can also be a disadvantage as it may not be possible to provide all the necessary nutrients or metabolic cofactors that would be present in vivo and, thus, may lead to incorrect conclusions (430). The major disadvantages of the model with respect to in vitro models include the lack of control of the extracellular fluid concentration for studies of drug efflux from the brain and a greater complexity that the brain matrix provides. As with other perfusion systems, this technique requires anes- thesia and thereby may act to confound results. These in situ techniques can be powerful tools to gauge the actual extent of P-gp efflux that can be expected in vivo. There are confounding factors that must be addressed when interpreting data obtained from these studies, and as with all biological models, the appropriate controls must be used to ensure that the observed effect appears to be due to P-gp-mediated efflux activity. In Vivo Models The major advantages to in vivo models are that they provide a method to understand relevance on an organism level and that these models have been used successfully to predict outcomes in humans. The obvious disadvantages of these models are their limitations with regards to study designs and sampling, reduced ability to deconvolute complex processes, and the need for animal experimenta- tion. For that reason, the in vivo model is a tool more suitable for aiding the understanding of the ramifications of P-gp efflux liability for gross disposition processes. A great deal of understanding around how P-gp affects disposition has come from in vivo models. Both gene products are expressed in the kidney, heart, lung, thymus, and spleen (12,444). The relative sequence identity of the human P-gp with the mouse mdr1a P-gp is 82% (227,446,447). The proteins show the least homology in the first extracellular loop, the connecting region between the homologous halves, and at both terminal ends (31,227,448). It was concluded that mdr1 P-gp has no essential physiological function, since no gross disturbance in corticosteroid metabolismduringpregnancyandinbileformationwasobservedinmdr1a (À/À) mice. However, lack of mdr1 P-gp significantly altered the disposition profile of P-gp substrates. In P-gp gene knockout mice, the absorption was increased, the elimination was decreased, and the concentration of certain substrates in key organs, such as the brain, testes, and heart, was increased dramatically (12). However, this and other transgenic models have not been widely employed in the evaluation of the effects of P-gp on drug pharmacokinetics. In Vivo/In Vitro Correlations In vitro models have provided invaluable information about properties of com- pounds that affect their in vivo transport and absorption. Regardless of how closely in vitro systems model in vivo conditions, they cannot completely rep- resent what may be seen in vivo by virtue of their reduced nature. For that reason, it is important to consider that a focused endpoint generated using an in vitro model will only correlate to a much more complex parameter like absorption when that endpoint is a major determinant of the complex parameter. The lack of in vitro/in vivo correlation does not necessarily implicate a failure of the model, but rather that the endpoint may not be sufficient to describe the in vivo process. Furthermore, the in vivo data used for these correlations are rarely The Role of P-Glycoprotein in Drug Disposition 405 precise or granular enough to gauge differences that may be related to P-gp efflux.
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