Research Articles
Physiologically Based Pharmacokinetic Modeling 1: Predicting the Tissue Distribution of Moderate-to-Strong Bases

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ABSTRACT:

Tissue-to-plasma water partition coefficients (Kpu's) form an integral part of whole body physiologically based pharmacokinetic (WBPBPK) models. This research aims to improve the predictability of Kpu values for moderate-to-strong bases (pKa  7), by developing a mechanistic equation that accommodates the unique electrostatic interactions of such drugs with tissue acidic phospholipids, where the affinity of this interaction is readily estimated from drug blood cell binding data. Additional model constituents are drug partitioning into neutral lipids and neutral phospholipids, and drug dissolution in tissue water. Major assumptions of this equation are that electrostatic interactions predominate, drugs distribute passively, and non-saturating conditions prevail. Resultant Kpu predictions for 28 moderate-to-strong bases were significantly more accurate than published equations with 89%, compared to 45%, of the predictions being within a factor of three of experimental values in rat adipose, bone, gut, heart, kidney, liver, muscle, pancreas, skin, spleen and thymus. Predictions in rat brain and lung were less accurate probably due to the involvement of additional processes not incorporated within the equation. This overall improvement in prediction should facilitate the further application of WBPBPK modeling, where time, cost and labor requirements associated with experimentally determining Kpu's have, to a large extent, deterred its application. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association

Section snippets

INTRODUCTION

Obtaining rapid information regarding the pharmacokinetics of new drug candidates is a bottleneck in the discovery and development of new drugs, while unfavourable parameters are a common reason for the failure of many compounds. To expedite the acquisition of pharmacokinetic data, assist compound selection and ultimately reduce compound failures, a sound understanding as to the behaviour of a compound within the test system is required. Such knowledge improves the ability to predict in vivo

Underlying Considerations

Previous work with the individual enantiomers of a series of eight β-blocking drugs suggested that plasma protein binding and acidic phospholipid (phosphatidylserine (PS), mono- and di-phosphatidylglycerol (PG), phosphatidylinositol (PI) and phosphatidic acid (PA)) concentrations in blood and tissue cells were the primary factors controlling the distribution of this drug class within the body.4 The dominant interaction between β-blockers (pKa of ca. 9.5) and acidic phospholipids is thought to

New Equation (Equation 19)

Overall, the accuracy of the Kpu predictions for 28 moderate-to-strong bases in 13 rat tissues (n = 261) was good, and little difference was observed between Kpu values predicted using experimental compared to predicted LogP and pKa values (Figures 2 and 3, Tables 3 and 4), with 85.1% compared to 86.3% of the predicted values being within a factor of three of experimentally determined Kpu's. Predictions of brain and lung Kpu values were less accurate with ca67% of the predictions agreeing with

DISCUSSION

At present the mechanistic equations used for Kpu predictions are deterministic, in that they compute a fixed mean with no measure of the inherent variability and uncertainty associated with the biological system and parameter determinations. So to assess the accuracy of the Kpu predictions point estimates have been compared with mean in vivo Kpu values, but due to the aforementioned variability and uncertainty the likelihood of these two values being identical is minimal. As such, an arbitrary

ACKNOWLEDGEMENTS

One of the authors (Dr Trudy Rodgers) thanks the BBSRC and Cyprotex, Macclesfield, Cheshire for their financial support in the form of a CASE studentship during the initial phases of this research, and the Centre for Applied Pharmacokinetic Research, University of Manchester for funding the continuation of this work.

REFERENCES (57)

  • B. Fichtl et al.

    Tissue binding versus plasma binding of drugs: General principles and pharmacokinetic consequences

    Adv Drug Res

    (1991)
  • N. Yata et al.

    Phosphatidylserine as a determinant for the tissue distribution of weakly basic drugs

    Pharm Res

    (1990)
  • Ansell GB, Hawthorne JN, editors. Phospholipids: Chemistry, metabolism and function, Vol. 3, 1st edition. Amsterdam:...
  • Ansell GB, Hawthorne JN, editors. Phospholipids: Chemistry, metabolism and function, Vol. 3, 1st edition. Amsterdam:...
  • K.G. Prasnnan

    Influence of age on the total lipid, phospholipid and cholesterol contents of pancreas and liver of albino rats

    Experientia

    (1973)
  • G. Rouser et al.

    Species variations in phospholipid class distribution of organs: I. Liver, kidney and spleen

    Lipids

    (1969)
  • B.J. Poorthuis et al.

    An improved two dimensional thin-layer chromatography system for the separation of phosphatidylglycerol and its derivatives

    J Lipid Res

    (1976)
  • R. Reinsso et al.

    Tissue water content in rats measured by desiccation

    J Pharmacol Meth

    (1997)
  • R.N. Pierson et al.

    Extracellular water measurements: Organ tracer kinetics of bromide and sucrose in rats and man

    Am J Physiol

    (1978)
  • R. Kawai et al.

    Physiologically based pharmacokinetic study on a cyclosporine derivative, SDZ IMM 125

    J Pharmacokin Biopharm

    (1994)
  • W.J. Waddell et al.

    Intracellular pH

    Physiol Rev

    (1969)
  • A. Nishiura et al.

    Role of acidic phospholipids in tissue distribution of quinidine in rats

    J Pharmaco-Dyn

    (1987)
  • J.M. Boon et al.

    Chemical control of phospholipid distribution across bilayer membranes

    Med Res Rev

    (2002)
  • P. Poulin et al.

    A biologically-based algorithm for predicting human tissue: blood partition coefficients of organic chemicals

    Hum Exp Toxicol

    (1995)
  • A.Y. Tehrani et al.

    Phosphorus-31 nuclear magnetic resonance studies of human red blood cells

    Blood Cells

    (1982)
  • D. Kummerow et al.

    Variations of intracellular pH in human erythrocytes via K+(Na+)/H+ exchange under low ionic strength

    J. Membrane Biol

    (2000)
  • B. Davies et al.

    Physiological parameters in laboratory animals and humans

    Pharm Res

    (1993)
  • Rowland M, Tozer TN, editors. Clinical pharmacokinetics: Concepts and applications, 3rd edition. Philadephia: Williams...
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