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The oriental dRTA families studied here contained three different band 3 mutations, the properties of which are summarized in Tables 4 and 5. The V850 and A858D mutations have not been described previously but two dRTA families carrying the G701D mutation have been found in Thailand [9, 10]. The G701D and V850 mutations show recessive inheritance of dRTA, which presents as pseudo-dominant inheritance in the presence of the SAO allele. The A858D mutation is dominant and the simple heterozygotes studied here have incomplete dRTA, an inability to acidify their urine but no accompanying features of dRTA [29, 32]. None of our patients was homozygous for the A858D mutation, but the compound heterozygotes of V850 and A858D showed full-blown dRTA.

The need for predictive models. The application of pharmacophore modeling to determine substrate or inhibitor specificity has greatly advanced our mechanistic understanding of drug transporters Chang and Swaan, 2005 ; . To date, several P-gp models derived from both efflux and inhibition data have been reported Ekins and Swaan, 2004; Chang and Swaan, 2005 ; , but application of these models to identify novel P-gp substrates or inhibitors has not been explored. Recently, Langer and colleagues Langer et al., 2004 ; described a P-gp pharmacophore that was subsequently utilized to screen molecular databases to select putative P-gp inhibitors. However, without in vitro validation of the predicted molecules, the impact of the work and the validity of the predictions remains to be demonstrated. To overcome limitations of previous studies, our present work applied three distinct P-gp pharmacophore models in database screening studies using the GH score as a metric for assessing the efficacy of the respective pharmacophore models Guner and Henry, 2000 ; . Specifically, the implementation of the GH score here can be used as a determinant of the effectiveness of the model in retrieving true and false positives from the database using standard search algorithms. Thus, the resulting hit lists simultaneously served as a means of model validation and assisted in the selection of molecules for subsequent in vitro testing. GH scores indicated that all three computational pharmacophore models, particularly the P-gp substrate model, were able to significantly enrich and successfully identify P-gp substrates from non-substrates Table 5 ; . Additionally, the two inhibitor pharmacophores were capable of retrieving a considerable and warfarin. 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