P. J. Neuvonen

The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin

AbstractObjective: To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment. Methods: Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on␣the␣last day of itraconazole administration, and 4 days␣later,␣and 15 mg 1 day and 4 days after the last dose␣of␣rifampicin.␣The disposition of midazolam and its α-hydroxy metabolite was determined and its pharmacodynamic effects were measured. Results: During itraconazole treatment, or 4 days after, α-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration–time curve (AUC0–∞) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng · h · ml−1), respectively. One day after rifampicin treatment, the AUC0–∞ of midazolam was 2.3% (i.e. 4.4 ng · h · ml−1) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC0–∞ was still only 13% (i.e. 27.1 ng · h · ml−1) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole and decreased by rifampicin. The ratio of plasma α-hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin than without treatment. Conclusion: Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment. After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least 4 days, probably even longer.

Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine

AbstractObjective: We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design. Methods: The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg · kg−1 was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole. Timed plasma samples were collected until 11 h. The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography. Results: The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo. Following itraconazole administration, t1/2 was 2.6 h. The values for plasma clearance and volume of distribution at steady state were similar during all the phases. Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC(0–11 h) by 45–60%. Conclusion: The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine.

Bacterial pneumonia can increase serum concentration of clozapine

Abstract. Concentrations of serum clozapine, c-reactive protein (CRP) and alpha1 acid glycoprotein were greatly increased during a bacterial pneumonia in a 53-year-old woman. As the pneumonia subsided, and CRP and alpha1 acid glycoprotein normalised, serum clozapine concentration also decreased to the previous level. An increased serum clozapine and a lowered N-desmethylclozapine to clozapine ratio during the infection suggest a decreased cytochrome P450 (CYP)1A2 activity. Cytokine-mediated CYP1A2 suppression is discussed.

Serum concentrations of clozapine and N-desmethylclozapine are unaffected by the potent CYP3A4 inhibitor itraconazole.

AbstractObjective: We studied a possible pharmacokinetic interaction between clozapine and itraconazole, a potent CYP3A4 inhibitor. Methods: A double-blind randomized study design was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 200 mg itraconazole or placebo for 7 days. For the next 7 days, itraconazole was changed to placebo and vice versa. Serum concentrations of clozapine and its main metabolite desmethylclozapine were measured on days 0, 3, 7, 10 and 14. Results: Concomitant administration of itraconazole had no significant effect on serum concentrations of clozapine or desmethylclozapine. Conclusion: CYP3A4 seems to be of minor importance in clozapine metabolism in humans. Itraconazole, and probably also other inhibitors of CYP3A4, can be used concomitantly with clozapine.

Sotalol prolongation of the QTc interval in hypertensive patients.

The effect of oral sotalol on the heart rate‐corrected QT interval (QTC) was studied in 33 hypertensive patients. Sotalol given once daily in doses of 160 to 640 mg prolonged the QTC interval in a concentration‐dependent manner by up to 150 msec (P < 0.001) over presotalol levels. The prolongation did not correlate with the initial length of the QTC interval. In seven patients with sotalol‐prolonged QTC interval, the withdrawal of sotalol for 3 days shortened the interval to nearly its original length. The effect of sotalol on PQ and QRS times was minimal. Sotalol seems to differ from other beta antagonists in having clear amiodarone‐like effects on the action potential of the heart after short‐ and long‐term administration. The measuring of the QTC interval is recommended if high sotalol concentrations are expected, since the risk of cardiac arrhythmias may increase.

Pharmacokinetics and pharmacodynamics of transdermal dexmedetomidine

Dexmedetomidine is a novel α2-adrenoceptor agonist that may provide beneficial effects as premedication for anesthesia. The pharmacokinetics and pharmacodynamics of transdermal (TD) and intravenous (IV) dexmedetomidine were studied in nine healthy male subjects in a crossover trial. The TD preparation, containing 625 μg of dexmedetomidine base, was applied on the forehead and left in place for 12 h. The IV dose (2.0 μg·kg-1 as dexmedetomidine hydrochloride) was administered as an infusion over 5 min. Dose-normalized total AUC values were used to calculate dexmedetomidine bioavailability. The bioavailability of dexmedetomidine from the TD preparation was 51%. However, the bioavailability of dexmedetomidine released from the preparation was 88%. The mean terminal half-life was 3.1 h after IV and 5.6 h after TD administration. After TD administration, the mean maximal reductions in blood pressure (systolic/diastolic) and heart rate were 28/20 mmHg and 19 beats·min-1. A sedative effect was obvious within 5 min and 1–2 h after IV and TD administration, respectively.

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone.

Objective:We studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic.Methods:A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 h.Results:Itraconazole significantly increased the Cmax of zopiclone from 49 to 63 ng ⋅ ml−1. The t1/2 of zopiclone was prolonged from 5.0 to 7.0 h. The AUC(0–∞) of zopiclone was increased from 415 to 719 ng ⋅ ml−1 h by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups.Conclusion:Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults.

Effect of food on the bioavailability of oxybutynin from a controlled release tablet.

Objective: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, Cmax, tmax, t1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined.Results: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20% . The Cmax of oxybutynin and N-desethyl oxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state.Conclusion: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.

Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite

AbstractObjective: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. Methods: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. Results: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0–t) and the peak concentration of oxybutynin twofold. The AUC0–t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. Conclusions: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.

EFFECT OF ACTIVATED CHARCOAL ON HYPERCHOLESTEROLAEMIA

Seven patients with hypercholesterolaemia were treated for 4 weeks with activated charcoal at a dose of 8 g three times a day. Plasma total cholesterol and LDL-cholesterol decreased by 25% and 41%, respectively, whereas HDL-cholesterol increased by 8%. Side-effects were negligible.