Pharmacokinetic relationships

One example of such constructive cross talk can be found in the growing literature on quantitative structure-pharmacokinetic relationships (QSPKR). Reports on how to predict pharmacokinetics from molecular information, or how to link pharmacokinetic parameters with molecular features, have appeared in both the pharmacokinetic [61] and the toxicological [62] literature. Others are extending this to pharmacodynamics as well [63], and the approaches look promising. 

Van der Graaf PH, Nilsson J, Van Schaick EA, Danhof M. Multivariate quantitative structure-pharmacokinetic relationships (QSPKR) analysis of adenosine A1 receptor agonists in rat. J Pharm Sci 1999 88 306-12. 

Fouchecourt MO, Beliveau M, Krishnan K. Quantitative structure-pharmacokinetic relationship modelling. Sci Total Environ 2001 274 125-35. 

Blakey GE, Nestorov lA, Arundel PA, Aarons LJ, Rowland M. Quantitative structure-pharmacokinetics relationships I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat. J Pharmacokinet Biopharm 1997 Jun 25(3) 277-312. Erratum in J Pharmacokinet Biopharm 1998 Feb 26(l) 131. 

Yap, C. W U, Z. R Chen, Y. Z. Quantitative strucmre-pharmacokinetic relationships for drug clearance by using statistical learning methods. /. Mol. Graph. Model. 2006, 24, 383-395. 

Physiologically based pharmacokinetic models provide a format to analyze relationships between model parameters and physicochemical properties for a series of drug analogues. Quantitative structure-pharmacokinetic relationships based on PB-PK model parameters have been pursued [12,13] and may ultimately prove useful in the drug development process. In this venue, such relationships, through predictions of tissue distribution, could expedite drug design and discovery. 

Toon, S., Rowland, M., Structure-pharmacokinetic relationships among the barbiturates in the rat, J. Pharmacol. Exp. Ther. 1983, 225, 752-763. 

Yap CW, Chen YZ (2005) Quantitative Structure-Pharmacokinetic Relationships for drug distribution properties by using general regression neural network. J Pharm Sci 94 153-168. 

Hasegawa, K., Shindoh, H., Shiratori, Y., Ohtsuka, T., Aoki, Y., Ichihara, S., Horii, L, and Shimma, N. Cassette dosing approach and quantitative structure-pharmacokinetic relationship study of antifungal N-myristoyl-transferaseinhibitors./. Chem. Inf. Comput. Sci. 2002, 42, 968—975. 

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]. 

Ghafourian, T, Barzegar-Jalali, M., Hakimha, N. and Cronin, M.T.D. (2004) Quantitative structure-pharmacokinetic relationship modeling apparent volume of distribution. Journal of Pharmacy and Pharmacology, 56, 339-350. 

Mattison LK, Fourie J, Hirao Y et al. The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity pharmacokinetic relationship between expired 13C02 and plasma [2-13C]dihydrouracil. Clin Cancer Pes 2006 12 549-555. 

A linear (pharmacokinetic) relationship between the dose (e.g., relevant clinical dose range) and measures of BA (area under the concenttation-time curve) of a drug is demonstrated in humans... 

Herman, R. A. and P. Veng-Pedersen. 1994. Quantitative structure-pharmacokinetic relationships for systemic drug distribution kinetics not con ned to a congeneric sefi harm. Sci83 423-428. 

Schaper, K. J. and J. K. Seydel. 1985. Multivariate methods in quantitative structure-pharmacokinetics relationship analysis. IrQSAR and Strategies in the Design of Bioactive CompquuHted by J. K. Seydel, pp. 173-189. Weinheim, Germany VCH. 

Ouantitative Structure-Activity Relationship Ouantitative Structure-Biodegradability Relationship Ouantitative Structure-Pharmacokinetic Relationship Ouantitative Structure-Property Relationship Multiple correlation coefficient and its square Relative Binding Affinity... 

Davis, A.M., Salt, D.W., and Webborn, P.J.H., Induced correlations in the use of unbound/intrinsic pharmacokinetic parameters in quantitative structure pharmacokinetic relationships with lipophilicity, Quant. Struct.-Act. Relat., 19, 574-580, 2000. 

Beliveau M, Krishnan K. 2005. A spreadsheet program for modeling quantitative structure-pharmacokinetic relationships for inhaled volatile organics in humans. SAR QSAR... 

Quantitative structure-activity/pharmacokinetic relationships (QSAR/ QSPKR) for a series of synthesized DHPs and pyridines as Pgp (type I (100) II (101)) inhibitors was generated by 3D molecular modelling using SYBYL and KowWin programs. A multivariate statistical technique, partial least square (PLS) regression, was applied to derive a QSAR model for Pgp inhibition and QSPKR models. Cross-validation using the leave-one-out method was performed to evaluate the predictive performance of models. For Pgp reversal, the model obtained by PLS could account for most of the variation in Pgp inhibition (R2 = 0.76) with fair predictive performance (Q2 = 0.62). Nine structurally related 1,4-DHPs drugs were used for QSPKR analysis. The models could explain the majority of the variation in clearance (R2 = 0.90), and cross-validation confirmed the prediction ability (Q2 = 0.69) [ 129]. 

Zhou XF, Shao Q, Coburn RA, Morris ME (2005) Quantitative structure-activity relationship and quantitative structure-pharmacokinetics relationship of 1,4-dihydropyridines and pyridines as multidrug resistance modulators. Pharm Res 22 1989-1996... 

However, drug substances for which /a may be affected by active transport processes [e.g., the efflux transporter P-glycoprotein (P-gp)] may require further model characterization to prevent misclassification of their permeability class. For example, functional expression of efflux transporters must be determined in cultured human or animal epithelial monolayers. At this time, the FDA recommends limiting the use of non-human permeability test methods to drug substances whose absorption is controlled by passive mechanisms. When applying the BCS, an apparent passive mechanism may be inferred when one of the following conditions is satisfied (i) a linear pharmacokinetic relationship between dose and a measure of bioavailability (e.g., area under the plasma concentration-time curve, AUC) is demonstrated in humans ... 

Pharmacodynamic and pharmacokinetic relationships in NSAID-induced acute kidney injury... 

For multi-source prescription medicines, comparative bioavailability data should be submitted showing the pharmacokinetic relationship of the product with the appropriate New Zealand Reference Product (NZRP). 

Karalis V, Tsantili-Kakoulidou A, and Macheras P (2003) Quantitative structure-pharmacokinetic relationships for disposition parameters of cephalosporins. European Journal of Pharmaceutical Sciences 20 115-123. 

Fig. 4.1 Fundamental pharmacokinetic relationships for repeated administration of drugs. This figure depicts the plasma drug concentrations produced by administering maintenance doses at a constant dosage interval (equal to the half-life of the drug). A plasma concentration within 90% of the eventual steady-state concentration is attained after approximately four half-lives of the drug.

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