Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone

The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone.; The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2 mg/kg).; Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo.; Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodone

Hemopressin and Other Bioactive Peptides from Cytosolic Proteins: Are These Non-Classical Neuropeptides?

Peptides perform many roles in cell–cell signaling; examples include neuropeptides, hormones, and growth factors. Although the vast majority of known neuropeptides are produced in the secretory pathway, a number of bioactive peptides are derived from cytosolic proteins. For example, the hemopressins are a family of peptides derived from alpha and beta hemoglobin which bind to the CB1 cannabinoid receptor, functioning as agonists or antagonists/inverse agonists depending on the size of the peptide. However, the finding that peptides derived from cytosolic proteins can affect receptors does not prove that these peptides are true endogenous signaling molecules. In order for the hemopressins and other peptides derived from cytosolic proteins to be considered neuropeptide-like signaling molecules, they must be synthesized in brain, they must be secreted in levels sufficient to produce effects, and either their synthesis or secretion should be regulated. If these criteria are met, we propose the name “non-classical neuropeptide” for this category of cytosolic bioactive peptide. This would be analogous to the non-classical neurotransmitters, such as nitric oxide and anandamide, which are not stored in secretory vesicles and released upon stimulation but are synthesized upon stimulation and constitutively released. We review some examples of cytosolic peptides from various protein precursors, describe potential mechanisms of their biosynthesis and secretion, and discuss the possibility that these peptides are signaling molecules in the brain, focusing on the criteria that these peptides would have to fill in order to be considered non-classical neuropeptides