CYP substrate

In addition, CYP substrates had permeation rates comparable to that of caffeine, a high-permeability, nonmetabolized, and completely absorbed... 

CYP Substrate classes Typical substrates Inhibitors Inducers Carcinogens activated... 

Some of the earliest QSAR studies on CYPs were performed by Basak (257), Murray (258), and Marshall (205). Gao et al. (259) explored the influence of electronic parameters of CYP substrates in 1996. The findings of Basak that electronic terms would cancel out have been proven wrong by many research papers published in the following decades. Tyrakowska et al. (260) indicated via QSARs based on calculated molecular orbital descriptors that the cat (maximum velocity converted per nmol of P450 per min) for CYP catalyzed C4-hydroxylation rates of aniline derivatives of different species (rats, rabbit, mice, and human) are closely related to the highest occupied molecular orbital energy (EHOMo)> r - 0-97. Several reviews published by Lewis et al. (212,216,228,261-265) and Ekins (240) should also be mentioned. 

The probe substrate should be specific/selective and the concentration should be at or below K. See Table 8.1 for a list of recommended CYP substrates. 

Table 4 The Effect of echinacea (400 mg q.i.d. x 8 days) on the Disposition of Prototypic CYP Substrates In Vivo...

Eszopiclone Bind selectively to a subgroup of GABAa receptors, acting like benzodiazepines to enhance membrane hyperpolarization Rapid onset of hypnosis with few amnestic effects or day-after psychomotor depression or somnolence Sleep disorders, especially those characterized by difficulty in falling asleep Oral activity short half-lives CYP substrates Toxicity Extensions of CNS depressant effects dependence liability Interactions Additive CNS depression with ethanol and many other drugs... 

Imipramine Mixed and variable blockade of NET and SERT Like SNRIs plus significant blockade of autonomic nervous system and histamine receptors Major depression not responsive to other drugs chronic pain disorders incontinence obsessive-compulsive disorder (clomipramine) Long half-lives CYP substrates active metabolites Toxicity Anticholinergic, G.-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose Interactions CYP inducers and inhibitors... 

Classified by the FDA as a strong inhibitor (i.e., caused a > 5-fold increase in plasma AUC or > 80% decrease in the clearance of CYP substrates in clinical evaluations)... 

The 3D homology model of the protein structure is validated as much as possible with experimental data, such as mutagenesis data, NMR spin-relaxation measurements (28-30), active site chemical probe studies (31,32), and predictions of CYP substrate- and/or inhibitor-binding and regioselective metabolism and... 

A strong inhibitor is one that causes a >fivefold increase in the plasma AUC values or more than 80% decrease in clearance of CYP substrates (not limited to sensitive CYP substrate) in clinical evaluations... 

A moderate inhibitor is one that causes a >two- but dosing interval in clinical evaluations. 

Terfenadine itself has no effect on CYP activity and thus does not affect metabolism of other CYP substrates. The drug-drug interactions of significance... 

Molecules are characterized by potential hydrogen bonding, polar, hydrophobic, and electrostatic interactions in 3D space, using 3D molecular fields. Techniques such as Comparative Molecular Field Analysis (CoMFA), which considers the 3D distribution of electrostatic and steric fields, have been applied to congeneric series of enzyme substrates or inhibitors generating 3D QSAR equations. Most examples of such applications are to modeling CYP substrate and inhibitor specificity and these have been extensively reviewed in the literature (Ekins et al., 2000 2001 Ter Laak and Vermeulen, 2001 Ter Laak et al., 2002). 

The lipophilicity parameter, log Kow, is generally greater than zero for CYP substrates or inducers. This is attributable, at least in part, to the fact that in most eukaryotic cells P450 is embedded in a phospholipid membrane across which a substrate has to travel (Lewis et al., 2001). 

CYP Substrate preferred acceptable Inhibitor preferred acceptable... 

Citalopram 40 mg/day for 4 weeks did not alter the pharmacokinetics of digoxin 1 mg orally (34). Digoxin is not a CYP substrate, so an interaction with SSRIs is unlikely, but the authors cited a report that fluoxetine increased plasma digoxin concentrations (35). 

The development of on-line combination of pulsed ultraliltration (PUF) and MS was reported by Van Breemen et al. [79-80]. Relevant CYP substrates, such as imipramine and chlorpromazine, were flow-injected into an ultrafiltration chamber, where rat liver microsomes were trapped in. Negative-ion ESl-MS was applied for the on-line detection of the metabolites. 

Sample preparation usually involves a protein precipitation cleanup step. Fast chromatography methods that provide run times of less than 2 min are generally preferred and attained. The LC-MS/MS method is optimized for each CYP substrate s metabolite SRM transition. The selectivity of MS/MS reduces the need for complete chromatographic resolution of individual components. Therefore, analytical run times are significantly reduced. Data analysis must be highly streamlined using automated data analysis and reporting. 

DRUG INTERACTIONS Chloramphenicol inhibits hepatic CYPs and thereby prolongs the half-hves of CYP substrates, including coumadin, phenytoin, chlorpropamide, HIV protease inhibitors, rifabutin, and tolbutamide. Severe toxicity and death have occurred due to these drug interactions. Concurrent administration ofphenobarbital or rifampin, which potently induce CYPs, shortens chloramphenicors t j and may result in subtherapeutic drug concentrations. 

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