Development of pharmacokinetic

Benzodiazepines do not induce their own metabolism, and thete is no evidence for the development of pharmacokinetic toletance (Gteenblatt and Shader 1986). The behavioral tolerance seen with chronic dosing is explicable entirely on the basis of pharmacodynamic tolerance (as described earlier in the overview of neuropharmacology). 

Hirabayashi, H., Nishikawa, M., Takakura, Y., and Hashida, M. Development of pharmacokinetics of galactosylated poly-L-glutamic acid as a biodegradable carrier for liver-specific drug delivery. Pharm. Res. 13 880-884, 1996. 

During the first decades of the development of pharmacokinetic science, a lag time in pharmacological response after intravenous administration was often treated by applying a compartmental approach. If the plasma concentration declined in a biexponential manner, the observed pharmacodynamic effect was fitted to plasma or tissue compartment concentrations. Due to the lag time of effects, a successful fit was sometimes obtained between effect and tissue drug level [414]. However, there is no a priori reason to assume that the time course of a drug concentration at the effect site must be related to the kinetics in tissues that mainly cause the multiexponential behavior of the plasma time-concentration course. A lag time between drug levels and dynamic effects can also occur for drugs described by a one-compartment model. 

Comparative Toxicokinetics. Qualitatively, absorption, distribution, metabolism, and excretion appear to be similar in humans and laboratory animals. However, quantitative variations in the absorption, distribution, metabolism, and excretion of benzene have been observed with respect to exposure routes, sex, nutritional status, and species. Further studies that focus on these differences and their implications for human health would be useful. Additionally, in vitro studies using human tissue and further research into PBPK modeling in animals would contribute significantly to the understanding of the kinetics of benzene and would aid in the development of pharmacokinetic models of exposure in humans. These topics are being addressed in ongoing studies (see Section 2.10.3). 

Obviously, one of the key tasks of a pharmacometrics service is the development of pharmacokinetic and pharmacodynamic models that serve as a mathematical representation of physiologic or pharmacologic phenomena. This is also one of the main activities that create a mockery of cost and schedule estimates. The complexity and scope of a pharmacometric model are limited only by the imagination, literature access, and computer resources of the pharmacometrician. Consequently, an effective model development process is one in which the extent of achievable... 

The focus of this book is primarily on the development of pharmacokinetic and pharmacokinetic-pharmacodynamic models. Models that are reported in the literature are not picked out of thin air. Useful models take time and effort and what is rarely shown is the process that went into developing that model. The purpose of this chapter is to discuss model development, to explain the process, and to introduce concepts that will be used throughout this book. Those criteria used to select a model extend to whether the model is a linear... 

Thus total clearance can be estimated by independently predicting each of the major clearance processes indicated. The liver is by far the main route of clearance for most drugs, therefore it has been the focus for much of the development of pharmacokinetic modeling methods. 

The development of new antibiotics to combat resistance, and to provide easier oral administration and improved pharmacokinetics has been successful through synthetic modifications. This approach has been particularly rewarding in the area of P-lactams. The commercial importance of the P-lactams is evident from Table 3 which gives the market share of antibacterials. Fully 62% of the 1989 world antibacterial market belonged to the cephalosporin and penicillin P-lactams (20). 

The realization of sensitive bioanalytical methods for measuring dmg and metaboUte concentrations in plasma and other biological fluids (see Automatic INSTRUMENTATION BlosENSORs) and the development of biocompatible polymers that can be tailor made with a wide range of predictable physical properties (see Prosthetic and biomedical devices) have revolutionized the development of pharmaceuticals (qv). Such bioanalytical techniques permit the characterization of pharmacokinetics, ie, the fate of a dmg in the plasma and body as a function of time. The pharmacokinetics of a dmg encompass absorption from the physiological site, distribution to the various compartments of the body, metaboHsm (if any), and excretion from the body (ADME). Clearance is the rate of removal of a dmg from the body and is the sum of all rates of clearance including metaboHsm, elimination, and excretion. 

An on-line chromatography/atmospheric pressure chemical ionization tandem mass spectrometry (LC-APCI/MS/MS) methods was developed for rapid screen of pharmacokinetics of different drugs, including 5 (98RCM1216). The electron impact mass spectrum of 5 and ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7Ff-pyrido[l,2,3- fe]-l,4-benzoxazine-6-carboxylate was reported (97MI28). Electron impact/Fourier transform... 

Over 4 decades, between 1960 and 2000, the development of new antibiotics used well characterized basic structures for partial synthetic modifications, primarily to overcome resistance by increasing the pharmacodynamic properties and, secondarily, to improve the pharmacokinetic profile of older compounds. However, bacteria rapidly responded by acquiring additional genetic alterations either as mutations or by accumulating resistance genes as part of mobile genetic elements ( integrons) on transferable resistance plasmids. 

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

Pharmacokinetic and Pharmacodynamic Aspects of Drug Development of Agents for... 

Hurwitz SJ, Schinazi RF (2002) Development of a pharmacodynamic model for HIV treatment with nucleoside reverse transcriptase and protease inhibitors. Antiviral Res 56 115-127 Hurwitz SJ, Tennant BC, Korba BE, Gerin JL, Schinazi RF (1998) Pharmacodynamics of (—)-beta-2, 3 -dideoxy-3 -thiacytidine in chronically virus-infected woodchucks compared to its pharmacodynamics in humans, Antimicrob Agents Chemother 42 2804-2809 Hurwitz SJ, Otto MJ, Schinazi RF (2005) Comparative pharmacokinetics of Racivir, (+/-)-beta-2, 3 -dideoxy-5-fluoro-3 -thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans, Antivir Chem Chemother 16 117-127... 

The potent activity of D-DOT against AZT- and 3TC-resistant HIV-1 strains together with its excellent pharmacokinetic profile in rhesus monkeys suggest that further development of D-DOT towards HIV-1 chemotherapy is warranted (Asif et al. 2007). 

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