Pharmacokinetics metabolic studies

There are two main reasons for entering the realm of micro- and nano-LC to obtain necessary sensitivity or if only the smallest quantities of samples are available. The main fields of application are currently proteomics, pharmacokinetics, metabolism studies, microdialysis, and, increasingly, environmental analysis. Flow rates in micro- (2-50 pL min ) and nano-LC (200-2000 nL min ) place high demands on the HPLC system and the user. Continuous optimization with regard to robustness, sensitivity, detection limit, and resolution tends to be a feature of any application. 

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

B. R., SB-242235, a selective inhibitor of p-38 mitogen-activated protein kinase. II in vitro and in vivo metabolism studies and pharmacokinetic extrapolation to man, Xenobiotica 2002, 32, 235—250. 

A landmark study reported that 40% of failures in clinical studies were due to PK problems.1-3 This led to the need to develop drug metabolism studies that could be performed on a compound before it was recommended for development. The early drug metabolism and pharmacokinetic (DMPK) studies were used to assess the ADME/PK properties of NCEs. The major pharmaceutical companies were very successful at setting up exploratory drug metabolism departments using various models. This led to an explosion of new higher throughput ADME/PK assays that provided medicinal chemists with the necessary tools to improve the ADME/PK properties of NCEs. 

As a possible alternative to in vitro metabolism studies, QSAR and molecular modelling may play an increasing role. Quantitative stracture-pharmacokinetic relationships (QSPR) have been studied for nearly three decades [42,45-52]. These are often based on classical QSAR approaches based on multiple linear regression. In its most simple form, the relationship between PK properties and lipophilicity has been discussed by various workers in the field [36, 49, 50]. 

P450 system In vitro drug metabolism studies have shown that solifenacin is a substrate of CYP3A4. Inducers or inhibitors of CYP3A4 may alter solifenacin pharmacokinetics. 

Pharmacokinetic (PK) studies in different animal species and additional in vitro studies provide information on the compound s predicted human PK parameters, including dose- and time-dependencies, its protein binding, the effect of food on its PK, and the cytochrome P450 isoenzymes responsible for its metabolism as well as the stmcture and activity of the main metabolites. Also a sensitive assay to quantify the compound and its metabolites in human blood and urine should have been developed and validated. 

Pharmacokinetics The study of a drug s absorption, distribution, metabolism, and excretion. 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

Because there is no human pharmacokinetic study evaluating this potential interaction or metabolic study data showing an effect of ginseng... 

The idea of back transformation of a three-dimensional NMR experiment involving heteronuclear 3H/X/Y out-and-back coherence transfer can in principle be carried to the extreme by fixing the mixing time in both indirect domains. Even if one-dimensional experiments of this kind fall short of providing any information on heteronuclear chemical shifts, they may still serve to obtain isotope-filtered 3H NMR spectra. A potential application of this technique is the detection of appropriately labelled metabolites in metabolism studies, and a one dimensional variant of the double INEPT 111/X/Y sequence has in fact been applied to pharmacokinetics studies of doubly 13C, 15N labelled metabolites.46 Even if the pulse scheme relied exclusively on phase-cycling for coherence selection, a suppression of matrix signals by a factor of 104 proved feasible, and it is easily conceivable that the performance can still be improved by the application of pulsed field gradients. 

Koup, J. R., Tucker, E., Thomas, D. J., Kinkel, A. W., Sedman, A. J., Dyer, R., Sharoky, M. A single and multiple dose pharmacokinetic and metabolism study of meclofenamate sodium, Biopharm. Drug Dispos. 1990, 11, 1-15. 

Pharmacokinetics The study of how the body handles drugs that is, the manner in which drugs are absorbed, distributed, metabolized, and excreted. 

A non-ribosomal biosynthetic pathway is clearly indicated for cyclosporin A, considering the uncommon structural elements MeBmt, L-a-aminobutyric acid and D-alanine as well as the plethora of isolated congeners [20,21]. Non-ribosomal biosynthesis directed by multienzyme thiotemplates have been reported for other small peptides of microbial origin, for example, gramicidin S [22] and enniatin [23]. Experimental data for cyclosporin A were obtained by feeding appropriate labelled precursors to cultures of T. inflation strains. The distribution profile of the labelled atoms in cyclosporin A was determined by 3H- or 13C-NMR spectroscopy. In preliminary trials with several tritium and carbon-14 labelled precursors, [met/y>/-3H]methionine proved to be the most suitable marker for the biosynthetic preparation of radiolabelled cyclosporin A for pharmacokinetic and metabolic studies [24],... 

Md.K. Pasha, S. Muzeeb, S.J.S. Basha, D. Shashikumar, R. Mullangi, N.R. Srinivas, Analysis of five HMG-CoA reductase inhibitors—atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin pharmacological, pharmacokinetic and analytical overview and development of a new method for use in pharmaceutical formulations analysis and in vitro metabolism studies, Biomed. Chromatogr. 20 (2006) 282-293. 

Drug metabolism and pharmacokinetic (DMPK) studies are used to show how the concentrations of the drug and its metabolites vary with the administered dose of the drug and the time from administration. They are normally carried out using suitable animal species and in humans in Phase I trials. The information obtained from animal studies is used to determine safe dose levels for use in the Phase I clinical trials in humans. However, the accuracy of the data obtained from animal tests is limited, since it is obtained by extrapolation. In addition, it is necessary to determine the dose that just saturates the absorption and elimination processes so that the toxicological and pharmacological events may be correctly interpreted. 

Finally, pharmacokinetics and metabolic studies are also available for TKIs at various stages of clinical development, including vatalanib [89-91], cediranib [92-94], and motesanib [95],... 

McGinnity DF, Riley RJ. Predicting drug pharmacokinetics in humans from in vitro metabolism studies. Biochem Soc Trans 2001 29 135-139. 

Kharasch ED, Whittington D, Hoffer C, et al. Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol importance of clinical investigations to validate in vitro drug metabolism studies. Clin Pharmacokinet 2005 44(7) 731-751. 

Pharmacological and metabolic studies on cannabinoids (Fig. 1) have suffered from a lack of knowledge of their physico-chemical properties and the insensitivity of assays of A -tetrahydrocannabinol 1, and its metabolites in biological fluids. Unambiguous, sensitive, specific and accurate quantification is required for forensic toxicology and pharmacokinetic studies which can be correlated with the time course of the psychoactive effects (2). 

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