Pregabalin enhances the antinociceptive effect of oxycodone and morphine in thermal models of nociception in the rat without any pharmacokinetic interactions.

BACKGROUND: Oxycodone is increasingly being used in combination with pregabalin. Pregabalin use is prevalent in opioid-dependent individuals. A high number of deaths caused by the co-use of gabapentinoids and opioids occur. It is not known whether pregabalin affects concentrations of oxycodone or morphine in the central nervous system. METHODS: Effects of pregabalin on acute oxycodone or morphine-induced antinociception, tolerance and sedation were studied using tail-flick, hot plate and rotarod tests in male Sprague-Dawley rats. Concentrations of pregabalin, opioids and their major metabolites in the brain were quantified by mass spectrometry. RESULTS: In the hot plate test, morphine (2.5 mg/kg, s.c.) caused antinociception of 28% maximum possible effect (MPE), whereas pregabalin (50 mg/kg, i.p.) produced 8-10% MPE. Co-administration of pregabalin and morphine resulted in antinociception of 63% MPE. Oxycodone (0.6 mg/kg s.c.) produced antinociception of 18% MPE, which increased to 39% MPE after co-administration with pregabalin. When pregabalin 10 mg/kg was administered before oxycodone (0.6 mg/kg, s.c.) or morphine (2.5 mg/kg), only the effect of oxycodone was potentiated in the tail-flick and the hot plate tests. Brain concentrations of the opioids, their major metabolites and pregabalin were unchanged. Pregabalin co-administration (50 mg/kg, i.p., once daily) did not prevent the development of morphine tolerance. CONCLUSIONS: Pregabalin potentiated antinociceptive and sedative effects of oxycodone and morphine in acute nociception. Co-administration of pregabalin with the opioids did not affect the brain concentrations of oxycodone or morphine. Pregabalin did not prevent morphine tolerance.

Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates.

BACKGROUND AND PURPOSE: Imatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Because competitive inhibition of CYP3A4/5 does not explain these in vivo interactions, we investigated the reversible and time-dependent inhibitory effects of imatinib and its main metabolite N-desmethylimatinib on CYP2C8 and CYP3A4/5 in vitro. EXPERIMENTAL APPROACH: Amodiaquine N-deethylation and midazolam 1'-hydroxylation were used as marker reactions for CYP2C8 and CYP3A4/5 activity. Direct, IC(50) -shift, and time-dependent inhibition were assessed with human liver microsomes. KEY RESULTS: Inhibition of CYP3A4 activity by imatinib was pre-incubation time-, concentration- and NADPH-dependent, and the time-dependent inactivation variables K(I) and k(inact) were 14.3 µM and 0.072 in(-1) respectively. In direct inhibition experiments, imatinib and N-desmethylimatinib inhibited amodiaquine N-deethylation with a K(i) of 8.4 and 12.8 µM, respectively, and midazolam 1'-hydroxylation with a K(i) of 23.3 and 18.1 µM respectively. The time-dependent inhibition effect of imatinib was predicted to cause up to 90% inhibition of hepatic CYP3A4 activity with clinically relevant imatinib concentrations, whereas the direct inhibition was predicted to be negligible in vivo. CONCLUSIONS AND IMPLICATIONS: Imatinib is a potent mechanism-based inhibitor of CYP3A4 in vitro and this finding explains the imatinib-simvastatin interaction and suggests that imatinib could markedly increase plasma concentrations of other CYP3A4 substrates. Our results also suggest a possibility of autoinhibition of CYP3A4-mediated imatinib metabolism leading to a less significant role for CYP3A4 in imatinib biotransformation in vivo than previously proposed.

Gemfibrozil markedly increases the plasma concentrations of montelukast: a previously unrecognized role for CYP2C8 in the metabolism of montelukast.

According to available information, montelukast is metabolized by cytochrome P450 (CYP) 3A4 and 2C9. In order to study the significance of CYP2C8 in the pharmacokinetics of montelukast, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 3 days, and 10 mg montelukast on day 3, in a randomized, crossover study. Gemfibrozil increased the mean area under the plasma concentration-time curve (AUC)(0-infinity), peak plasma concentration (C(max)), and elimination half-life (t(1/2)) of montelukast 4.5-fold, 1.5-fold, and 3.0-fold, respectively (P < 0.001). After administration of gemfibrozil, the time to reach C(max) (t(max)) of the montelukast metabolite M6 was prolonged threefold (P = 0.005), its AUC(0-7) was reduced by 40% (P = 0.027), and the AUC(0-24) of the secondary metabolite M4 was reduced by >90% (P < 0.001). In human liver microsomes, gemfibrozil 1-O-beta glucuronide inhibited the formation of M6 (but not of M5) from montelukast 35-fold more potently than did gemfibrozil (half-maximal inhibitory concentration (IC(50)) 3.0 and 107 micromol/l, respectively). In conclusion, gemfibrozil markedly increases the plasma concentrations of montelukast, indicating that CYP2C8 is crucial in the elimination of montelukast.

The effect of gemfibrozil on repaglinide pharmacokinetics persists for at least 12 h after the dose: evidence for mechanism-based inhibition of CYP2C8 in vivo.

Repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and 3A4. Gemfibrozil has the effect of increasing the area under the concentration-time curve (AUC) of repaglinide eightfold. We studied the effect of dosing interval on the extent of the gemfibrozil-repaglinide interaction. In a randomized five-phase crossover study, 10 healthy volunteers ingested 0.25 mg repaglinide, with or without gemfibrozil pretreatment. Plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. When the last dose of 600 mg gemfibrozil was ingested simultaneously with repaglinide, or 3, 6, or 12 h before, it increased the AUC(0-infinity) of repaglinide 7.0-, 6.5-, 6.2- and 5.0-fold, respectively (P < 0.001). The peak repaglinide concentration increased approximately twofold (P < 0.001), and the half-life was prolonged from 1.2 h to 2-3 h (P < 0.001) during all the gemfibrozil phases. The drug interaction effects persisted at least 12 h after gemfibrozil was administered, although plasma gemfibrozil and gemfibrozil 1-O-beta-glucuronide concentrations were only 5 and 10% of their peak values, respectively. The long-lasting interaction is likely caused by mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide.

Gemfibrozil considerably increases the plasma concentrations of rosiglitazone.

AIMS/HYPOTHESIS: Our aim was to investigate possible interaction between gemfibrozil and rosiglitazone, a thiazolidinedione antidiabetic drug. METHODS: In a randomised crossover study with two phases, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 4 days. On day 3, they ingested a single 4 mg dose of rosiglitazone. Plasma rosiglitazone and its N-desmethyl metabolite concentrations were measured for up to 48 h. RESULTS: Gemfibrozil raised the mean area under the plasma rosiglitazone concentration-time curve (AUC) 2.3-fold (range 1.5- to 2.8-fold; p=0.00002) and prolonged the elimination half-life (t(1/2)) of rosiglitazone from 3.6 to 7.6 h ( p=0.000002). The peak plasma rosiglitazone concentration (C(max)) was increased only 1.2-fold (range 0.9- to 1.6-fold; p=0.01) by gemfibrozil, but gemfibrozil raised the plasma rosiglitazone concentration measured 24 h after dosing (C(24)) 9.8-fold (range, 4.5- to 33.6-fold; p=0.00008). In addition, gemfibrozil prolonged the t(max) of N-desmethylrosiglitazone from 7 to 12 h and reduced the N-desmethylrosiglitazone/rosiglitazone AUC(0-48) ratio by 38% ( p<0.01). CONCLUSIONS/INTERPRETATION: Gemfibrozil raises the plasma concentrations of rosiglitazone probably by inhibiting the CYP2C8-mediated biotransformation of rosiglitazone. Co-administration of gemfibrozil, or another potent inhibitor of CYP2C8, and rosiglitazone could increase the efficacy but also the risk of concentration-dependent adverse effects of rosiglitazone.

Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate.

BACKGROUND: Concomitant use of fibrates with statins has been associated with an increased risk of myopathy, but the underlying mechanism of this adverse reaction remains unclear. Our aim was to study the effects of bezafibrate and gemfibrozil on the pharmacokinetics of lovastatin. METHODS: This was a randomized, double-blind, 3-phase crossover study. Eleven healthy volunteers took 400 mg/day bezafibrate, 1200 mg/day gemfibrozil, or placebo for 3 days. On day 3, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, gemfibrozil, and bezafibrate were measured up to 24 hours. RESULTS: Gemfibrozil markedly increased the plasma concentrations of lovastatin acid, without affecting those of the parent lovastatin compared with placebo. During the gemfibrozil phase, the mean area under the plasma concentration-time curve from 0 to 24 hours [AUC(0-24)] of lovastatin acid was 280% (range, 131% to 1184%; P < .001) and the peak plasma concentration (Cmax) was 280% (range, 123% to 1042%; P < .05) of the corresponding value during the placebo phase. Bezafibrate had no statistically significant effect on the AUC(0-24) or Cmax of lovastatin or lovastatin acid compared with placebo. CONCLUSIONS: Gemfibrozil markedly increases plasma concentrations of lovastatin acid, but bezafibrate does not. The increased risk of myopathy observed during concomitant treatment with statins and fibrates may be partially of a pharmacokinetic origin. The risk of developing myopathy during concomitant therapy with lovastatin and a fibrate may be smaller with bezafibrate than with gemfibrozil.

Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride.

OBJECTIVE: Our objective was to study the effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride, a new sulfonylurea antidiabetic drug. METHODS: In this randomized, double-blind, three-phase crossover study, 12 healthy volunteers took 200 mg of fluconazole once daily (400 mg on day 1), 100 mg of fluvoxamine once daily, or placebo once daily for 4 days. On day 4, a single oral dose of 0.5 mg of glimepiride was administered. Plasma glimepiride and blood glucose concentrations were measured up to 12 hours. RESULTS: In the fluconazole phase, the mean total area under the plasma concentration-time curve of glimepiride was 238% (P <.0001) and the peak plasma concentration was 151% (P <.0001) of the respective control value. The mean elimination half-life of glimepiride was prolonged from 2.0 to 3.3 hours (P <.0001) by fluconazole. In the fluvoxamine phase, the mean area under the plasma concentration-time curve of glimepiride was not significantly different from that in the placebo phase. However, the mean peak plasma concentration of glimepiride was 143% (P <.05) of the control and the elimination half-life was prolonged from 2.0 to 2.3 hours (P <.01) by fluvoxamine. Fluconazole and fluvoxamine did not cause statistically significant changes in the effects of glimepiride on blood glucose concentrations. CONCLUSIONS: Fluconazole considerably increased the area under the plasma concentration-time curve of glimepiride and prolonged its elimination half-life. This was probably caused by inhibition of the cytochrome P-450 2C9-mediated biotransformation of glimepiride by fluconazole. Concomitant use of fluconazole with glimepiride may increase the risk of hypoglycemia as much as would a 2- to 3-fold increase in the dose of glimepiride. Fluvoxamine moderately increased the plasma concentrations and slightly prolonged the elimination half-life of glimepiride.

Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations.

BACKGROUND: Rifampin (rifampicin) is a potent inducer of several cytochrome P450 (CYP) enzymes, including CYP3A4. The cholesterol-lowering drug simvastatin has an extensive first-pass metabolism, and it is partially metabolized by CYP3A4. This study was conducted to investigate the effect of rifampin on the pharmacokinetics of simvastatin. METHODS: In a randomized cross-over study with two phases and a washout of 4 weeks, 10 healthy volunteers received a 5-day pretreatment with rifampin (600 mg daily) or placebo. On day 6, a single 40-mg dose of simvastatin was administered orally. Plasma concentrations of simvastatin and its active metabolite simvastatin acid were measured up to 12 hours with a sensitive liquid chromatography-ion spray tandem mass spectrometry method. RESULTS: Rifampin decreased the total area under the plasma concentration-time curve of simvastatin and simvastatin acid by 87% (P < .001) and 93% (P < .001), respectively. Also the peak concentrations of both simvastatin and simvastatin acid were reduced greatly (by 90%) by rifampin (P < .001). On the other hand, rifampin had no significant effect on the elimination half-life of simvastatin or simvastatin acid. CONCLUSIONS: Rifampin greatly decreases the plasma concentrations of simvastatin and simvastatin acid. Because the elimination half-life of simvastatin was not affected by rifampin, induction of the CYP3A4-mediated first-pass metabolism of simvastatin in the intestine and the liver probably explains this interaction. Concomitant use of potent inducers of CYP3A4 can lead to a considerably reduced cholesterol-lowering efficacy of simvastatin.

Determination of buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP) in human plasma by capillary gas chromatography.

Two separate gas chromatographic methods for the determination of buspirone and its active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP) in human plasma are described. Both procedures involve solid-phase extraction (the packing material of the cartridges used was C8 for buspirone and a mixed-mode sorbent for 1-PP), injection of the sample into a gas chromatograph equipped with a fused-silica capillary column and a nitrogen-phosphorus detector, and analysis with temperature programming (from 220 degrees C to 285 degrees C for buspirone and from 138 degrees C to 285 degrees C for 1-PP). The coating material of the analytical column was 5% diphenyl dimethyl silicone for buspirone and 50% diphenyl dimethyl silicone for 1-PP. Zolpidem was used as an internal standard in the buspirone assay and 1-phenylpiperazine in the 1-PP assay. Recovery of buspirone and 1-PP averaged 98% and 89%, respectively, and the limit of quantification was 0.2 ng/mL for both compounds. The between-run coefficients of variation ranged from 3.2% to 9.4% and from 2.9% to 8.6% for samples spiked with three different concentrations of buspirone and 1-PP, respectively. The suitability of these assays for pharmacokinetic studies was shown by analyzing timed plasma samples from volunteers after ingestion of a single therapeutic dose of buspirone (10 mg).

Pharmacokinetics of intravenous N-acetylcysteine in pre-term new-born infants.

BACKGROUND: Reactive oxygen species have been considered to play a role in several clinical complications in pre-term infants. The aim of this study was to determine the pharmacokinetics of intravenous N-acetylcysteine in pre-term neonates. This information is needed to evaluate the use of N-acetylcysteine as an antioxidant in this patient group. METHODS: N-acetylcysteine was infused intravenously in ten patients (gestational age 24.9-31.0 weeks, weight 500-1384 g) for 24 h (3.4-4.6 mg/kg/h), starting 2.0-11.2 h from birth (study I) and in six patients (gestational age 25.9-29.7 weeks, weight 520-1335 g) for 6 days (0.3-1.3 mg/kg/h), starting at the age of 24 h (study II). Arterial plasma N-acetylcysteine and cyst(e)ine concentrations were determined from timed samples taken during (study I and II) and after (study I) the N-acetylcysteine infusion. RESULTS: In study I, the mean elimination half-life of N-acetylcysteine was 11 h (range 7.8-15.2 h). The mean plasma clearance of N-acetylcysteine was 37 ml/kg/h (range 13-62 ml/kg/h) and the mean volume of distribution was 573 ml/kg (range 167-1010 ml/kg). The plasma clearance and volume of distribution correlated with weight (r = 0.81, P < 0.01, and r = 0.78, P < 0.01, respectively) and with gestational age (r = 0.71, P < 0.05, and r = 0.64, P < 0.05, respectively). In study II, the steady-state concentration of N-acetylcysteine was reached in 2-3 days in five of six patients during a constant infusion. CONCLUSIONS: The pharmacokinetics of N-acetylcysteine in pre-term infants depend markedly on weight and gestational age. The elimination of N-acetylcysteine is much slower in pre-term new-borns than in adults.

The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone.

OBJECTIVE: The effects of fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor antidepressant, on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated. METHODS: In a randomized, placebo-controlled, two-phase cross-over study, ten healthy volunteers took either 100 mg fluvoxamine or matched placebo orally once daily for 5 days. On day 6, 10 mg buspirone was taken orally. Plasma concentrations of buspirone and its active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), were measured up to 18 h and the pharmacodynamic effects of buspirone up to 8 h. RESULTS: The total area under the plasma buspirone concentration-time curve was increased 2.4-fold (P < 0.05) and the peak plasma buspirone concentration 2.0-fold (P < 0.05) by fluvoxamine, compared with placebo. The half-life of buspirone was not affected. The ratio of the total area under the plasma concentration-time curve of 1-PP to that of buspirone was decreased from 7.4 [6.3 (SD)] to 4.4 (3.6) by fluvoxamine (P < 0.05). The results of the six pharmacodynamic tests remained unchanged. CONCLUSION: Fluvoxamine moderately increased plasma buspirone concentrations and decreased the production of the active 1-PP metabolite of buspirone. The mechanism of this interaction is probably inhibition of the CYP3A4-mediated first-pass metabolism of buspirone by fluvoxamine. However, this pharmacokinetic interaction was not associated with impairment of psychomotor performance and it is probably of limited clinical significance.

Serum and muscle tissue ubiquinone levels in healthy subjects.

Ubiquinone, or coenzyme Q, is a mitochondrial component with antioxidant properties. It has been suggested that ubiquinone therapy may have clinical benefits in some diseases with mitochondrial dysfunction and that the antioxidant effects could be useful, for example, in the prevention of atherosclerosis. Based on this clinical interest, guidelines for the interpretation of ubiquinone analyses are needed. Our results show that serum and muscle ubiquinone levels vary over a wide range in healthy subjects. The serum levels of ubiquinone depend mostly on the amount of ubiquinone-containing lipoproteins in circulation. Physical activity markedly affects muscle tissue levels of ubiquinone. We observed that serum and muscle tissue ubiquinone levels do not correlate with each other, suggesting that they are independently regulated.