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We describe a comprehensive retrospective analysis in which the abilities of several methods by which human pharmacokinetic parameters are predicted from preclinical pharmacokinetic data and/or in vitro metabolism data were assessed. The prediction methods examined included both methods from the scientific literature as well as some described in this report for the first time. Four methods were examined for their ability to predict human volume of distribution. Three were highly predictive, yielding, on average, predictions that were within 60% to 90% of actual values. Twelve methods were assessed for their utility in predicting clearance. The most successful allometric scaling method yielded clearance predictions that were, on average, within 80% of actual values. The best methods in which in vitro metabolism data from human liver microsomes were scaled to in vivo clearance values yielded predicted clearance values that were, on average, within 70% to 80% of actual values. Human t1/2 was predicted by combining predictions of human volume of distribution and clearance. The best t1/2 prediction methods successfully assigned compounds to appropriate dosing regimen categories (e.g., once daily, twice daily and so forth) 70% to 80% of the time. In addition, correlations between human t1/2 and t1/2 values from preclinical species were also generally successful (72-87%) when used to predict human dosing regimens. In summary, this retrospective analysis has identified several approaches by which human pharmacokinetic data can be predicted from preclinical data. Such approaches should find utility in the drug discovery and development processes in the identification and selection of compounds that will possess appropriate pharmacokinetic characteristics in humans for progression to clinical trials.

We have analyzed LSXSS recumbinant inbred for ethanol-induced activity using 2.0 g/kg ethanol and a new method we call ethanol activation slope. The ethanol activation slope provides a robust dose-response measure of ethanol activation, independent of both activity after saline and the inhibitory effects of ethanol on locomotor activity. These behavioral data were used in a quantitative trait locus analysis to map chromosomal loci involved in ethanol-induced locomotor activity. We tentatively identified seven loci that mediate the low-dose stimulatory effect of ethanol and six loci involved in locomotion after 2.0 g/kg ethanol. Only one of the loci are in common between the two behaviors. We also compared the behavioral quantitative trait locus to those previously identified that are involved in regulating central nervous system neurotensin levels and neurotensin receptor densities. Six chromosomal regions were identified that regulate at least one central nervous system neurotensin measure and an ethanol-induced locomotor behavior. The identification of loci controlling both central nervous system neurotensin levels or neurotensin receptor densities and ethanol-induced locomotor activity strengthens the proposal that neurotensin regulates, in part, ethanol-induced behaviors and central nervous system sensitivity to ethanol.

Sensitivity to the hypnotic effects of ethanol was increased selectively by central administration of muscarinic agonists. Carbachol or oxotremorine, but not nicotine, i.c.v., enhanced hypnotic sensitivity to ethanol markedly, as measured by blood ethanol concentration at loss or righting response, in short-sleep (SS) but not long-sleep (LS) mice. Likewise, the acetylcholinesterase inhibitor, neostigmine, i.c.v., differentially enhanced hypnotic sensitivity to ethanol in these mouse lines. LS and SS mice were equally sensitive to the hypothermic effects of carbachol, neostigmine or oxotremorine i.c.v. The muscarinic antagonists, atropine or pirenzepine, i.c.v., were without effect on ethanol sensitivity, but these compounds antagonized muscarinic agonist-enhanced ethanol sensitivity in SS mice effectively. Pirenzepine, and M1 selective antagonist, produced a parallel shift in the oxotremorine dose-response curve, indicating that the enhanced hypnotic sensitivity to ethanol may be due to interaction of oxotremorine with M1 muscarinic receptors. This possibility was supported by the finding that atropine and pirenzepine which are known to have comparable affinities for M1 but not M2 receptors, had comparable potencies in antagonizing the action of oxotremorine or neostigmine. The results suggest that LS and SS mice differ genetically in neuronal processes activated by specific muscarinic agonists and are consistent with the hypotheses that ethanol acts in part via membrane receptor coupling to intracellular processes known to mobilize intracellular Ca++.