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The transmembrane energy-dependent efflux transporter P-glycoprotein (P-gp) limits a range of drugs from penetrating cells and deposits them into the extracellular space. P-gp is highly expressed in several normal tissues, including the luminal surface of capillary endothelial cells in the brain of humans. In this study, we tested whether olanzapine distribution to tissues highly expressing P-gp or devoid of this transporter was similar in Abcb1a (-/-) mice lacking P-gp and control animals. At 1 h following the intraperitoneal injection of 2.5 microg olanzapine/g mouse, olanzapine concentrations were statistically and significantly higher in brain (three-fold), liver (2.6-fold), and kidney (1.8-fold) of Abcb1a (-/-) mice than those of the control FVB Abcb1a (+/+) mice, and not statistically different in plasma, spleen, or penile tissue. Similar differences were also found for the ratios of organ:plasma and organ:spleen between the two groups. This is the first report that the presence of the Abcb1a gene is an important factor controlling brain access to olanzapine. The finding that the brain penetration of olanzapine is limited by P-gp implies that the highly prevalent functional polymorphisms of ABCB1 in humans may be a factor contributing to variability in dose requirements for this antipsychotic drug.

An elevation of I1 (imidazoline-1)-binding sites on platelets may be a state marker for depression. Herein, platelet I1 sites were compared in two groups of unipolar depressed patients given different regimens of bupropion treatment: Regimen 1 (n = 13 titrated up to 300 mg/d by week 4 and held constant until week 6); Regimen 2 (n = 15 titrated up to 300 mg/d by week 2, to 450 mg/d by week 6, and held constant until week 8). Platelet I1 sites were quantified by p-[125I]iodoclonidine binding (0.5-15 nM) and displaced by moxonidine under a saturating concentration of norepinephrine to mask alpha2-adrenoceptors. I1 B max values were confirmed to be high at pretreatment in depressed patients (n = 28) compared to healthy control subjects (n = 18; p = 0.02). Highest B max values at pretreatment were found in patients who responded worst to treatment. More than two-thirds of patients recovered from depression (69 and 80% in Regimens 1 and 2, respectively) after treatment. Dose and/or time of exposure to bupropion were relevant variables since (1). only Regimen 2 led to platelet I1 down-regulation and (2). the extent of down-regulation correlated with plasma concentrations of bupropion. The data suggest a dissociation exists between I1 down-regulation and therapeutic response, or else platelet I1 down-regulation lags behind clinical antidepressant response before becoming measurable.