Therapeutic drug monitoring of plasma clozapine and of its principal plasma metabolite N-desmethylclozapine (norclozapine) (predose or "trough" sample) can help in monitoring adherence, in dose adjustment, and in minimizing the risk of toxicity. To obtain data to assist in the interpretation of analytical results, the results from a clozapine therapeutic drug monitoring service, 1993-2007, have been audited. There were 104,127 samples from 26,796 patients [18,750 (70%) men aged at time of first sample (median, range) 34 (10-89) years, and 7763 (30%) female aged 38 (12-90) years]. Clozapine was not detected (plasma concentration <0.01 mg/L) in 1.5% of samples (prescribed clozapine dose up to 900 mg/d). Plasma clozapine was either below 0.35 mg/L or greater than 0.60 mg/L in 42.5% and 28.4% of samples, respectively; in 0.4% samples plasma clozapine was 2.0 mg/L or more. Although plasma clozapine was broadly related to prescribed dose, there was much variation: 1.2% of samples had plasma clozapine >1.0 mg/L at prescribed clozapine doses up to 150 mg/d (76.2% < 0.35 mg/L), whereas 23.3% of samples had plasma clozapine < 0.35 mg/L at doses of 850 mg/d and over (18.0% > 1.0 mg/L). The highest plasma clozapine and norclozapine concentrations encountered were 4.95 and 2.45 mg/L, respectively. Although the median plasma clozapine:norclozapine ratio was 1.25 at plasma clozapine concentrations < 0.35 mg/L, the median ratio was 2.08 at plasma clozapine concentrations > 1.0 mg/L. Data (median, 10th-90th percentile) for both clozapine and norclozapine by prescribed clozapine dose band are useful in assessing partial adherence. Analysis of the plasma clozapine:norclozapine ratio by clozapine concentration provides clear evidence that clozapine N-demethylation becomes saturated at higher plasma clozapine concentrations and adds urgency to the requirement for dose adjustment should smoking habit change. A clozapine:norclozapine ratio greater then 2 suggests either a nontrough sample, or that clozapine N-demethylation has become saturated.
A biochemical approach is utilised in the study of the maintenance of variation at the Adh locus in Drosophila melanogaster. There is a direct correlation between biochemical findings and the results of competition experiments. The relevance of these findings to the study of other enzyme polymorphisms is discussed.
The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoidsFbut this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region ( + 31%; p ¼ 0.045); in contrast, in abcb1ab (À/À) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (À45%; p ¼ 0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (À/À) mice, but in abcb1ab (À/À) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (À/À) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the 'physiological' levels of untreated mice (À39%; p ¼ 0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (À9 to À23%), but had no effect on 11b-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.
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