Teijo I. Saari

Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam.

Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam.

Rifampin Greatly Reduces the Plasma Concentrations of Intravenous and Oral Oxycodone

Background:Oxycodone is a &mgr;-opioid receptor agonist that is metabolized mainly in the liver by cytochrome P450 3A and 2D6 enzymes. Rifampin is a strong inducer of several drug-metabolizing enzymes. The authors studied the interaction of rifampin with oxycodone. Their hypothesis was that rifampin enhances the CYP3A-mediated metabolism of oxycodone and attenuates its pharmacologic effect. Methods:The protocol was a four-session, paired crossover. Twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days. Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity. Results:Rifampin decreased the area under the oxycodone concentration–time curve of intravenous and oral oxycodone by 53% and 86%, respectively (P < 0.001). Oral bioavailability of oxycodone was decreased from 69% to 21% (P < 0.001). Rifampin greatly increased the plasma metabolite–to–parent drug ratios for noroxycodone and noroxymorphone (P < 0.001). Pharmacologic effects of oral oxycodone were attenuated. Conclusions:Induction of cytochrome P450 3A by rifampin reduced the area under the oxycodone concentration–time curve of intravenous and oral oxycodone. The pharmacologic effects of oxycodone were modestly attenuated. To maintain adequate analgesia, dose adjustment of oxycodone may be necessary, when used concomitantly with rifampin.

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABAAR) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABAARs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABAARs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABAARs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABAAR agonist remimazolam, have recently been published.

Role of transforming growth factor β in testicular immunosuppression

Abstract The potential role of transforming growth factor β (TGFβ) in the regulation of the immunological milieu of the testis was investigated. Antibodies neutralizing TGFβ reversed the previously observed suppression of rat peripheral blood lymphocyte proliferation induced by rat abdominal testis extract. Recombinant TGF β 1 dose-dependently inhibited testicular interleukin-1-like factor-driven proliferation of murine thymocytes and ConA-stimulated rat peripheral blood mononuclear cells. Extracts of seminiferous tubules contained a M r ∼25 K TGFβ-like growth inhibitor of the CLL-64 mink lung epithelial cell line. The present findings suggest an important role for TGFβ in testicular immunosuppression.

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-d-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(−)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.

Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Oxycodone is an opioid analgesic that is metabolized mainly in the liver by cytochrome P450 (CYP) 2D6 and 3A4 enzymes. So far, the effects of CYP2D6 or CYP3A4 inhibitors on the pharmacokinetics of oxycodone in humans have not been systematically studied. WHAT THIS STUDY ADDS Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone. When both of CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially. AIM The aim of this study was to find out whether the inhibition of cytochrome P450 2D6 (CYP2D6) with paroxetine or concomitant inhibition of CYP2D6 and CYP3A4 with paroxetine and itraconazole, altered the pharmacokinetics and pharmacological response of orally administered oxycodone. METHODS A randomized placebo-controlled cross-over study design with three phases was used. Eleven healthy subjects ingested 10 mg of oral immediate release oxycodone on the fourth day of pre-treatment with either placebo, paroxetine (20 mg once daily) or paroxetine (20 mg once daily) and itraconazole (200 mg once daily) for 5 days. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacological (analgesic and behavioural) effects were evaluated. RESULTS Paroxetine alone reduced the area under concentration-time curve (AUC(0,0-48 h)) of the CYP2D6 dependent metabolite oxymorphone by 44% (P < 0.05), but had no significant effects on the plasma concentrations of oxycodone or its pharmacological effects when compared with the placebo phase. When both oxidative pathways of the metabolism of oxycodone were inhibited with paroxetine and itraconazole, the mean AUC(0,infinity) of oxycodone increased by 2.9-fold (P < 0.001), and its C(max) by 1.8-fold (P < 0.001). Visual analogue scores for subjective drug effects, drowsiness and deterioration of performance were slightly increased (P < 0.05) after paroxetine + itraconazole pre-treatment when compared with placebo. CONCLUSIONS Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone if the function of the CYP3A4 pathway is normal. When both CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially.

Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone

BackgroundThe aim of this study was to investigate the effects of the cytochrome P450 3A4 (CYP34A) inhibitor itraconazole on the pharmacokinetics and pharmacodynamics of orally and intravenously administered oxycodone.MethodsTwelve healthy subjects were administered 200 mg itraconazole or placebo orally for 5 days in a four-session paired cross-over study. On day 4, oxycodone was administered intravenously (0.1 mg/kg) in the first part of the study and orally (10 mg) in the second part. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacodynamic effects were evaluated.ResultsItraconazole decreased plasma clearance (Cl) and increased the area under the plasma concentration–time curve (AUC0–∞) of intravenous oxycodone by 32 and 51%, respectively (P < 0.001) and increased the AUC(0–∞) of orally administrated oxycodone by 144% (P < 0.001). Most of the pharmacokinetic changes in oral oxycodone were seen in the elimination phase, with modest effects by itraconazole on its peak concentration, which was increased by 45% (P = 0.009). The AUC(0–48) of noroxycodone was decreased by 49% (P < 0.001) and that of oxymorphone was increased by 359% (P < 0.001) after the administration of oral oxycodone. The pharmacologic effects of oxycodone were enhanced by itraconazole only modestly.ConclusionsItraconazole increased the exposure to oxycodone by inhibiting its CYP3A4-mediated N-demethylation. The clinical use of itraconazole in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid-associated adverse effects.

St John’s wort greatly reduces the concentrations of oral oxycodone

Background: Chronic pain is associated with depression. Self‐treatment of depression with herbal over‐the‐counter medicine St Johns wort makes pain patients prone to drug interactions.

Grapefruit Juice Enhances the Exposure to Oral Oxycodone

Grapefruit juice alters the concentrations of many CYP3A substrates. The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross-over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration-time curve (AUC(0-∞) ) by 1.7-fold (p<0.001), the peak plasma concentration by 1.5-fold (p<0.001) and the half-life of oxycodone by 1.2-fold (p<0.001) as compared to the water. The metabolite-to-parent AUC(0-∞) ratios (AUC(m)/AUC(p) ) of noroxycodone and noroxymorphone decreased by 44% (p<0.001) and 45% (p<0.001), respectively. Oxymorphone AUC(0-∞) increased by 1.6-fold (p<0.01) after grapefruit juice, but the AUC(m)/AUC(p) remained unchanged. Pharmacodynamic changes were modest and only self-reported performance significantly impaired after grapefruit juice. Analgesic effects were not influenced. Grapefruit juice inhibited the CYP3A4-mediated first-pass metabolism of oxycodone, decreased the formation of noroxycodone and noroxymorphone and increased that of oxymorphone. We conclude that dietary consumption of grapefruit products may increase the concentrations and effects of oxycodone in clinical use.

Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study

BACKGROUND Oxycodone is a µ-opioid receptor agonist, the global use of which has increased vigorously during the past decade. The pharmacokinetic data of oxycodone available for elderly are limited, and there appear to be only little data on the population pharmacokinetics of oxycodone. METHODS We analysed 1272 plasma oxycodone samples of 77 individuals (range of age 19-89 yr) with non-linear mixed effect modelling. Inter- and intra-individual variability of the model was estimated for clearances and distribution volumes. The effect of covariates was studied with simulations. RESULTS Data were best described with a two-compartment linear model. Lean body mass and age were found to be significant covariates for elimination clearance and the volume of the central compartment. The population estimates of elimination clearance, volume of the central compartment, and the volume of distribution at steady state for a reference individual (male 35 yr, 70 kg, 170 cm) were 51.0 litre h(-1), 134, and 258 litres, respectively. The elimination half-life of oxycodone showed an age-dependent increase. The context-sensitive half-time at steady state increased from 3.8 to 4.6 h between the age of 25 and 85 yr, respectively. Simulations of repetitive bolus dosing showed a 20% increase in oxycodone concentration in the elderly. CONCLUSIONS Age was found to be a significant covariate for oxycodone pharmacokinetics. In elderly patients, dosing should therefore be reduced and carefully titrated to avoid considerable accumulation of oxycodone and potentially hazardous side-effects.