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0090-9556/06/3404-727-$20.00
DMD 34:727-, 2006

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LETTER

RESPONSE TO "BINDING OF DRUGS TO HEPATIC MICROSOMES: COMMENT AND ASSESSMENT OF CURRENT PREDICTION METHODOLOGY WITH RECOMMENDATION FOR IMPROVEMENT"

R. P. Austin, P. Barton, and R. J. Riley

Department of Physical and Metabolic Science, AstraZeneca R&D Charnwood, Loughborough, United Kingdom

(Received December 23, 2005; accepted January 11, 2006)

We are pleased to see the enlarged set of microsome binding data and are encouraged by the performance of our earlier equation when applied to the additional data. Furthermore, the modified equation derived by Houston and Hallifax does appear to perform better and certainly removes bias in the estimates of binding for neutrals and bases. Our only concern is to caution that care must be taken in using such a quadratic model for compounds with values of logD/P which lie outside of the range of the training set. This is particularly true for compounds with logD/P <–2, where the quadratic model will predict an increase in binding with a decrease in lipophilicity, whereas the linear model will predict a vanishingly small amount of binding which we feel is more likely. However, we have not yet carried out extensive measurements on such polar compounds to demonstrate this unequivocally.

Regarding the comments relating to our hepatocyte binding work: while we accept that the dataset for hepatocyte binding is smaller than that for microsome binding, and that any functional membrane transport activity present will affect the free concentration of compound in addition to any nonspecific binding processes, we feel that the equation we derived at least has utility in estimating the component of hepatocyte binding due to nonactive processes. For many compounds this will be the dominant process, and was so for the 17 compounds we studied, and we have found that prediction of hepatocyte binding using our reported equation does improve the quality of clearance predictions. Of course, we would welcome any future expansion of the hepatocyte binding dataset, as has been done with the microsome binding dataset, to provide an important external validation of our method.


   Footnotes
 
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

doi:10.1124/dmd.105.009142.

Address correspondence to: R. P. Austin, Department of Physical and Metabolic Science, AstraZeneca R&D Charnwood, Loughborough, UK. E-mail: rupert.austin{at}astrazeneca.com





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