Pharmacokinetics predictions from

Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Ranee DJ, Wastall P. The prediction of human pharmacokinetic parameters from precl-inical and in vitro metabolism data. J Pharmacol Exp Ther 1997 Oct 283(l) 46-58... 

T. E., Silber, M., Jones, B. C., MacIntyre, F., Rance, D. J., Wastall, P., The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data, J. Pharmacol. Exp. Ther. 1997,... 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

The pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

Interroute Extrapolation. The Corley model used three routes of administration, intraperitoneal, oral and inhalation, in rats and mice to describe the disposition of chloroform. This data was validated for humans by comparing the model output using the animal data with actual human data from human oral chloroform pharmacokinetic studies. Using the human pharmacokinetic constants from the in vitro studies conducted by Corley, the model made adequate predictions of the amount of chloroform metabolized and exhaled in both males and females. 

Neural networks are a relatively new tool in data modelling in the field of pharmacokinetics [54—56]. Using this approach, non-linear relationships to predicted properties are better taken into account than by multiple linear regression [45]. Human hepatic drug clearance was best predicted from human hepatocyte data, followed by rat hepatocyte data, while in the studied data set animal in vivo data did not significantly contribute to the predictions [56]. 

Pharmacokinetics and metabolism - absorption, distribution, metabolism and excretion (ADME), including potential for interactions, polymorphisms of drug metabolising enzymes and exposures in man predicted from interspecies allometric scaling... 

Finally, no discussion of human pharmacokinetic predictions is complete without a consideration of allometric scaling [67-69]. In general, allometry is the examination of relationships between size and function and it has been applied to the prediction of human pharmacokinetic parameters from animal pharmacokinetic parameters for decades [70]. Allometry has been shown to work reasonably well for predicting human VD from animal VD data, probably because volumes of plasma and various tissue across species are allometrically scaleable to body weight, a notion reinforced... 

Caldwell, G.W., Masucci, J.A., Yan, Z. and Hageman, W. (2004) Allometric scaling of pharmacokinetic parameters in drug discovery Can human CL Vss and tl/2 be predicted from in-vivo rat data European Journal of Drug Metabolism and Pharmacokinetics, 29, 133-143. 

Mahmood, 1. (1999) Prediction of clearance, volume of distribution and half-life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants a comparative study. Journal of Pharmacy and Pharmacology, 51, 905-910. 

There appear to be gender differences in the pharmacokinetics of selective benzodiazepines such as chlordiazepoxide and diazepam. As would be predicted from studies evaluating the effect of OCs on various P450 enzymes, the levels of hydroxylated and demethylated benzodiazepines are increased in OC users, and the levels of conjugated benzodiazepines are decreased in OC users. Importantly, however, the pharmacokinetic effect may not always predict the impairment on psychomotor and cognitive tasks seen in women who are concurrently given OCs and benzodiazepines. 

Drug interactions are normally considered as pharmacokinetic or pharmacodynamic, or they may be grouped according to the site at which the interaction takes place. Many drug interactions can be predicted from the knowledge of the principles of pharmacokinetics and of the mode of action of the drugs concerned, and so this chapter should be read in conjunction with the chapters which describe these principles. 

Toxicity is a major cause for the withdrawal of drugs from the market and it is a major concern for pharmaceutical researchers. Reactive metabolism is certainly a very hot topic within the whole approach to drug metabolism. The downstream consequences of not identifying reactive metabolites may be financially catastrophic. There is an increasing drive to have early prediction of the metabolic fate and interactions of candidate drug molecules. Factors such as metabolic stability, toxic metabolite production, and P450 inhibition and induction are all routinely monitored to prevent compounds with poor pharmacokinetic properties from progressing forward onto clinical trials. 

Although the impact of gender and high age on the pharmacokinetics of the developmental drug can be studied based on single-dose data as described, the use of steady-state data can be required if there is reason to believe that the pharmacokinetics of the drug studied are not accurately predictable from single-dose data. 

Houston JB, Galetin A. 2003. Progress towards prediction of human pharmacokinetic parameters from in vitro technologies. Drug Metab Rev 35 393-415. 

Frequency of dosing in pracfice is often greater than predicted from half-life, as durafion of biological acfivify is offen shorter than pharmacokinetic terminal half-life... 

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