Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174

Objective: Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, whereas fluconazole affects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of these antimycotics with losartan in healthy volunteers. Methods: A randomised, double-blind, three-phase crossover study design was used. Eleven healthy volunteers ingested orally, once a day for 4 days, either itraconazole 200 mg, fluconazole (400 mg on day 1 and 200 mg on days 2–4) or placebo (control). On day 4, a single 50-mg oral dose of losartan was ingested. Plasma concentrations of losartan, E-3174, itraconazole, hydroxy-itraconazole and fluconazole were determined over 24 h. The blood pressure and heart rate were also recorded over 24 h. Results: The mean peak plasma concentration (C_max) and area under the curve [AUC(0∞)] of E-3174 were significantly decreased by fluconazole to 30% and to 47% of their control values, respectively, and the t_1/2 was increased to 167%. Fluconazole caused only a nonsignificant increase (23–41%) in the AUC and t_1/2 of the unchanged losartan. Itraconazole had no significant effect on the pharmacokinetic variables of losartan or E-3174. The ratio AUC(0∞)_E-3174/AUC(0∞)_losartan was 60% smaller during the fluconazole than during the placebo and itraconazole phases. No clinically significant changes in the effects of losartan on blood pressure and heart rate were observed between fluconazole, itraconazole and placebo phases. Conclusion: Fluconazole but not itraconazole interacts with losartan by inhibiting its metabolism to the active metabolite E-3174. This implicates that, in man, CYP2C9 is a major enzyme for the formation of E-3174 from losartan. The clinical significance of the fluconazole–losartan interaction is unclear, but the possibility of a decreased therapeutic effect of losartan should be kept in mind. Received: 4 June 1997 / Accepted in revised form: 10 September 1997     

Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam

Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC_0–3, AUC_0–17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (C_max) 2- to 2.5-fold compared with placebo. The AUC_0–3 and the C_max of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. Conclusion: We conclude that the metabolism of orally␣administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole. Received: 1 July 1996 / Accepted in revised form: 4 September 1996     

The effect of itraconazole on the pharmacokinetics and pharmacodynamics of oral prednisolone

Objective: To examine the possible effect of itraconazole on the pharmacokinetics and pharmacodynamics of orally administered prednisolone. Methods: In this double-blind, randomised, two-phase cross-over study, ten healthy subjects received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, 20 mg prednisolone was given orally. Plasma concentrations of prednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined by means of high-performance liquid chromatography up to 47 h. Results: Itraconazole increased the total area under the plasma prednisolone concentration–time curve by 24% (P < 0.001) and the elimination half-life of prednisolone by 29% (P < 0.001) compared with placebo. The peak plasma concentration and time to the peak of prednisolone were not affected by itraconazole. The mean morning plasma cortisol concentration, measured 23 h after the ingestion of prednisolone, during the itraconazole phase was 73% of that during the placebo phase (P < 0.001). Conclusions: The observed minor interaction between itraconazole and oral prednisolone is probably of limited clinical significance. The susceptibility of prednisolone to interact with CYP3A4 inhibitors is considerably smaller than that of methylprednisolone, and itraconazole and probably also other inhibitors of CYP3A4 can be used concomitantly with prednisolone without marked changes in the effects of this corticosteroid. Received: 4 October 1999 / Accepted in revised form: 29 November 1999     

Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition

Objective: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same conditions. Methods: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to 0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours. Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1–2 and 6–7, and twice daily on study days 3–5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1–2 and 6–7 were compared with each other. Results: There were no differences in maximal plasma concentration (C_max), time to maximal drug concentration in plasma (t_max), elimination half-life (t_1/2) and area under the plasma concentration–time curve (AUC) of entacapone between day 1 and day 6. The mean t_1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant. No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosing of entacapone. There were no between-day differences in C_max, t_1/2 (2.4 h on days 1–2 and 2.3 h on days 6–7) or AUC of levodopa, whereas t_max occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (C_max, t_max and AUC) of carbidopa. Conclusion: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity. Received: 28 December 1998 / Accepted in revised form: 29 March 1999     

Concomitant use of mirtazapine and cimetidine: a drug–drug interaction study in healthy male subjects

Objective: The objective of this study was to examine the pharmacokinetics and the tolerability/safety of mirtazapine and cimetidine separately and in combination following oral administration of multiple doses. Methods: This was a double-blind, placebo-controlled, two-period cross-over, multiple-dose pharmacokinetic interaction study in 12 healthy male subjects. They received either cimetidine (800 mg b.i.d.) or placebo in combination with (commercially available, racemic) mirtazapine (30 mg nocte). Cimetidine and placebo were administered for 14 days, with mirtazapine added during days 6–12 of each period. Serial blood samples for kinetic profiling were taken on day 5 and day 12 for cimetidine and on days 12–14 for mirtazapine. Results: The co-administration of cimetidine resulted in a statistically significant increase in the area under the curve (AUC_0–24) and C_max of mirtazapine (54% and 22% respectively). The AUC_0–24 of demethylmirtazapine increased only slightly, and there was no effect on C_max. The elimination half-lives for both mirtazapine and its demethyl metabolite were unaffected by cimetidine co-administration. The trough and average plasma concentrations during the steady state were elevated during cimetidine treatment (62% and 54%, respectively). Mirtazapine had no effect on the pharmacokinetics of cimetidine. Conclusion: Co-administration of cimetidine (800 mg b.i.d.) and mirtazapine (30 mg nocte) resulted in increased steady-state plasma levels of mirtazapine (C_ss,min= +61%, P < 0.05; C_ss,av=+54%, P < 0.05), probably as a result of increased bio-availability. The C_max (+22%, P < 0.05) and AUC_0–24 (+54%, P < 0.05) also increased. Due to the variability of the mirtazapine plasma levels in patients, the clinical meaning of these increases is probably limited. Co-administration of mirtazapine did not alter cimetidine pharmacokinetics. Received: 24 November 1999 / Accepted in revised form: 15 May 2000     

Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl

Objective Fentanyl is a widely used opioid analgesic, which is extensively metabolized by hepatic cytochrome P450 (CYP) 3A. Recent reports suggest that concomitant administration of CYP3A inhibitors with fentanyl may lead to dangerous drug interactions. Methods The potential interactions of fentanyl with triazole antifungal agents voriconazole and fluconazole were studied in a randomized crossover study in three phases. Twelve healthy volunteers were given 5 μg/kg of intravenous fentanyl without pretreatment (control), after oral voriconazole (400 mg twice on the first day and 200 mg twice on the second day), or after oral fluconazole (400 mg once on the first day and 200 mg once on the second day). Plasma concentrations of fentanyl, norfentanyl, voriconazole, and fluconazole were determined up to 24 h. Pharmacokinetic parameters were calculated using compartmental methods. Results The mean plasma clearance of intravenous fentanyl was decreased by 23% (range −22 to 48%; p < 0.05) and 16% (−34 to 53%; p < 0.05) after voriconazole and fluconazole administration, respectively. Voriconazole increased the area under the fentanyl plasma concentration-time curve by 1.4-fold (p < 0.05). The initial plasma concentrations and volume of distribution of fentanyl did not differ significantly between phases. Conclusion Both voriconazole and fluconazole delay the elimination of fentanyl significantly. Caution should be exercised, especially in patients who are given voriconazole or fluconazole during long-lasting fentanyl treatment, because insidiously elevated fentanyl concentration may lead to respiratory depression.     

Grapefruit juice can increase the plasma concentrations of oral methylprednisolone

Objective: To investigate whether the pharmacokinetics of orally administered methylprednisolone and plasma cortisol concentrations are affected by administration of grapefruit juice. Methods: In a randomised, two-phase, cross-over study, ten healthy subjects received either 200 ml double-strength grapefruit juice or water three times a day for 2 days. On day 3, 16 mg methylprednisolone was given orally with 200 ml grapefruit juice or water. Additionally, 200 ml grapefruit juice or water was ingested 0.5 h and 1.5 h after methylprednisolone administration. Plasma concentrations of methylprednisolone and cortisol were determined using liquid chromatography/mass spectrometry (LC/MS/MS) over a 47-h period. Results: Grapefruit juice increased the total area under the plasma methylprednisolone concentration–time curve (AUC_0–∞) by 75% (P < 0.001) and the elimination half-life (t _1/2) of methylprednisolone by 35% (P < 0.001). The peak plasma concentration of methylprednisolone (C_max) was increased by 27% (P < 0.01). Grapefruit juice delayed the time to the C_max from 2.0 h to 3.0 h (P < 0.05). There was no significant difference in the plasma cortisol concentrations, measured after methylprednisolone administration, between the water and grapefruit juice phases. However, grapefruit juice slightly decreased the morning plasma cortisol concentrations before methylprednisolone administration (P < 0.05). Conclusions: Grapefruit juice given in high amounts moderately increases the AUC_0–∞ and t _1/2 of oral methylprednisolone. The increase in t _1/2 suggests that grapefruit juice can affect the systemic methylprednisolone metabolism. The clinical significance of the grapefruit juice–methylprednisolone interaction is small, but in some sensitive subjects high doses of grapefruit juice might enhance the effects of oral methylprednisolone. Received: 17 February 2000 / Accepted in revised form: 9 May 2000     

Effect of itraconazole on cerivastatin pharmacokinetics

Objective: To determine the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of cerivastatin, a competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methods: A randomized, double-blind, cross-over study design with two phases, which were separated by a wash-out period of 4 weeks, was used. In each phase ten healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days according to a randomization schedule. On day 4, 0.3 mg cerivastatin was administered orally. Serum concentrations of cerivastatin, its major metabolites, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 24 h. Results: Itraconazole increased the area under the concentration-time curve from time zero to infinity (AUC_0–∞) of the parent cerivastatin by 15% (P < 0.05). The mean peak serum concentration (C_max) of cerivastatin lactone was increased 1.8-fold (range 1.1-fold to 2.4-fold, P < 0.001) and the AUC_0–24 h 2.6-fold (range 2.0-fold to 3.6-fold, P < 0.001) by itraconazole. The elimination half-life (t_1/2) of cerivastatin lactone was increased 3.2-fold (P < 0.001). Itraconazole decreased the AUC_0–24 h of the active M-1 metabolite of cerivastatin by 28% (P < 0.05), whereas the AUC_0–24 h of the more active metabolite, M-23, was increased by 36% (P < 0.05). The AUC_0–24 h and t_1/2 of active HMG-CoA reductase inhibitors were increased by 27% (P < 0.05) and 40% (P < 0.05), respectively, by itraconazole. Conclusions: Itraconazole has a modest interaction with cerivastatin. Inhibition of the CYP3A4-mediated M-1 metabolic pathway leads to elevated serum concentrations of cerivastatin, cerivastatin lactone and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors. Received: 28 June 1998 / Accepted in revised form: 10 October 1998     

Stereoselective interaction between the CYP2C8 inhibitor gemfibrozil and racemic ibuprofen

Objective Ibuprofen, a nonsteroidal anti-inflammatory agent, is metabolised in vitro by cytochrome P450 (CYP) 2C8 and 2C9. We studied the possible effect of gemfibrozil, an in vivo inhibitor of CYP2C8, on the pharmacokinetics of ibuprofen in healthy volunteers. Methods In a randomised two-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each subject ingested 400 mg of racemic ibuprofen. Plasma concentrations of ibuprofen enantiomers and gemfibrozil were measured. Results Gemfibrozil raised the mean total area under the plasma concentration-time curve (AUC_0–∞) of R-ibuprofen by 34% (range −10 to 67%; P < 0.001). The elimination half-lives (t _1/2) of R- and S-ibuprofen were increased by 54 and 34% (range 11–162% and 16–85%; P < 0.001) respectively. The other pharmacokinetic variables of R- and S-ibuprofen were not changed significantly. The AUC_0–∞ ratio of R-ibuprofen to S-ibuprofen was increased by gemfibrozil (P < 0.001). Conclusions Gemfibrozil moderately increases the AUC_0–∞ of R-ibuprofen and prolongs its t _1/2, indicating that R-ibuprofen is partially metabolised by CYP2C8. The interconversion of R- to S-ibuprofen can explain the small effect of gemfibrozil on the t _1/2 of S-ibuprofen. The gemfibrozil-ibuprofen interaction is of limited clinical significance.     

Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin

Objectives: To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin. Methods: Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5–10 mg on days 2–21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15–21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (C_max), time to reach C_max (t_max), the area under the concentration–time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the C_min of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21). Results: Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma C_min concentrations of S-warfarin and irbesartan were also not affected. Conclusions: No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary. Received: 10 December 1998 / Accepted in revised form: 29 June 1999     

Grapefruit juice has no effect on quinine pharmacokinetics

Objective: As quinine is mainly metabolised by human liver CYP3A4 and grapefruit juice inhibits CYP3A4, the effect of grapefruit juice on the pharmacokinetics of quinine following a single oral dose of 600 mg quinine sulphate was investigated. Methods: The study was carried out in ten healthy volunteers using a randomised cross-over design. Subjects were studied on three occasions, with a washout period of 2 weeks. During each period, subjects received a pretreatment of 200 ml orange juice (control), full-strength grapefruit juice or half-strength grapefruit juice twice daily for 5 days. On day 6, the subjects were given a single oral dose of 600 mg quinine sulphate with 200 ml of one of the juices. Plasma and urine samples for measurement of quinine and its major metabolite, 3-hydroxyquinine, were collected over a 48-h period and analysed by means of a high-performance liquid chromatography method. Results: The intake of grapefruit juice did not significantly alter the oral pharmacokinetics of quinine. There were no significant differences among the three treatment periods with regard to pharmacokinetic parameters of quinine, including the peak plasma drug concentration (C_max), the time to reach C_max (t_max), the terminal elimination half-life (t_1/2), the area under the concentration–time curve and the apparent oral clearance. The pharmacokinetics of the 3-hydroxyquinine metabolite were slightly changed when volunteers received grapefruit juice. The mean C_max of the metabolite (0.25 ± 0.09 mg l⁻¹, mean ± SD) while subjects received full-strength grapefruit juice was significantly less than during the control period (0.31 ± 0.06 mg l⁻¹, P < 0.05) and during the intake of half-strength grapefruit juice (0.31 ± 0.07 mg l⁻¹, P < 0.05). Conclusion: These results suggest that there is no significant interaction between the parent compound quinine and grapefruit juice, so it is not necessary to advise patients against ingesting grapefruit juice at the same time that they take quinine. Since quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on quinine pharmacokinetics supports the view that the site of CYP inhibition by grapefruit juice is mainly in the gut. Received: 2 November 1998 / Accepted in revised form: 18 February 1999     

Effect of grapefruit juice dose on grapefruit juice–triazolam interaction: repeated consumption prolongs triazolam half-life

Objective: Grapefruit juice inhibits CYP3A4-mediated metabolism of several drugs during first pass. In this study, the effect of grapefruit juice dose on the extent of grapefruit juice–triazolam interaction was investigated. Methods: In a randomised, four-phase, crossover study, 12 healthy volunteers received 0.25 mg triazolam with water, with 200 ml normal-strength or double-strength grapefruit juice or, on the third day of multiple-dose [three times daily (t.i.d.)] administration of double-strength grapefruit juice. Timed blood samples were collected up to 23 h after dosing, and the effects of triazolam were measured with four psychomotor tests up to 10 h after dosing. Results: The area under the plasma triazolam concentration–time curve (AUC_0–∞) was increased by 53% (P < 0.01), 49% (P < 0.01) and 143% (P < 0.001) by a single dose of normal-strength, a single dose of double-strength and multiple-dose administration of double-strength grapefruit juice, respectively. The peak plasma concentration (C_max) of triazolam was increased by about 40% by a single dose of normal-strength grapefruit juice (P < 0.01) and multiple-dose grapefruit juice (P < 0.01) and by 25% by a single dose of double-strength grapefruit juice (P < 0.05). The elimination half-life (t _1/2) of triazolam was prolonged by 54% during the multiple-dose grapefruit juice phase (P < 0.001). A significant increase in the pharmacodynamic effects of triazolam was seen during the multiple-dose grapefruit juice phase in the digit symbol substitution test (DSST, P < 0.05), in subjective overall drug effect (P < 0.05) and in subjective drowsiness (P < 0.05). Conclusions: Even one glass of grapefruit juice increases plasma triazolam concentrations, but repeated consumption of grapefruit juice produces a significantly greater increase in triazolam concentrations than one glass of juice. Thet _1/2 of triazolam is prolonged by repeated consumption of grapefruit juice, probably due to inhibition of hepatic CYP3A4 activity. Received: 30 December 1999 / Accepted in revised form: 11 April 2000     

Influence of renal function on the pharmacokinetics of cerivastatin in normocholesterolemic adults

Objective: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this non-randomized, non-blinded, 7-day, multiple-dose study. Methods: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CL_CR >90 ml/min/1.73 m², n=9), or patients with either mild (CL_CR 61 ml/min/1.73 m² to ≤90 ml/min/1.73 m², n=9), moderate (CL_CR 30 ml/min/1.73 m² to ≤60 ml/min/1.73 m², n=8), or severe (CL_CR <30 ml/min/1.73 m², but not on dialysis, n=9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin, including the area under the concentration–time curve (AUC)_0–24, peak plasma concentration (C_max), time to reach C_max (t_max) and elimination half-life (t_1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices. Results: The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 μg/h/l vs 19.2 μg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40–60% higher (30.8 μg/h/l and 29.0 μg/h/l, respectively). C_max values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 μg/l, respectively. This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved in the United States. The mean t_1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation. This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the mean AUC and C_max values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease. Conclusion: This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal impairment is likely unnecessary. Received: 2 August 1999 / Accepted in revised form: 12 January 2000     

Fluvoxamine but not citalopram increases serum melatonin in healthy subjects – an indication that cytochrome P 450 CYP1A2 and CYP2C19 hydroxylate melatonin

Objective: The nocturnal serum melatonin (MT) level increases after ingestion of fluvoxamine (FLU) – a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unknown. Citalopram (CIT) is another SSRI. It is not known whether CIT affects the serum MT level. It may well be that these two compounds affect serum MT levels differently, inasmuch as the ways they inhibit cytochrome P ₄₅₀ (CYP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP enzymes are probably involved in the hepatic metabolism of MT. If FLU, but not CIT, inhibits liver enzymes involved in the metabolism of MT, different serum MT concentrations should probably ensue. The objective of this investigation was to test this hypothesis. Methods: Seven healthy subjects participated in three different experiments, which were performed in random order 6–8 days apart. In experiment A, placebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. All doses were given orally at 1600 hours. Serum MT concentrations were determined at regular intervals between 1600 hours and noon next day (20 h). Plasma concentrations of CIT were measured repeatedly in experiment B, and plasma FLU concentrations in experiment C. MT areas under the curve representing the 20-h period (MT-AUC_0–20) were compared in the three experiments, and differences were statistically evaluated. Results: FLU augmented the MT-AUC_0–20 by a factor of 2.8 compared with the effect of placebo (P < 0.01), whereas CIT was without significant effect. More MT was excreted in the urine after ingestion of FLU than after placebo. In contrast, CIT did not influence the MT excretion. A clear relationship was found between serum levels of MT and plasma concentrations of FLU. Conclusion: The serum MT level increased markedly after ingestion of FLU but not after CIT. The exact mechanism behind this finding is unknown, but decreased hepatic metabolism of MT by either CYP1A2 or CYP2C19, or both, is probable. Although exogenous MT, causing high MT concentration in plasma, has sleep-promoting properties in man, it is at this stage unknown whether serum MT concentrations in the range found in this study have similar effects. This has to be given further attention in additional studies. Received: 25 October 1999 / Accepted in revised form: 2 February 2000     

Induction of cytochrome P450 2B6 activity by the herbal medicine baicalin as measured by bupropion hydroxylation

Purpose  This study investigated the effect of the herbal medicine baicalin on bupropion hydroxylation, a probe reaction for CYP2B6 activity related to different CYP2B6 genotype groups. Method  Seventeen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6, and 5 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with baicalin. Blood samples were taken up to 72 h after each bupropion dose, and pharmacokinetics profiles were determined on days 1 and 25 for bupropion and hydroxybupropion. Result  Baicalin administration increased hydroxybupropion maximum plasma concentration (C _max) by 73% [90% confidence interval (CI), 44–108%; P < 0.01] and the area under the concentration time curve extrapolated to infinity (AUC_0–∞) of hydroxybupropion by 87% (90% CI, 48–137%; P < 0.01), with no change in the elimination half-life of hydroxybupropion. Baicalin increased the AUC_0–∞ ratio of hydroxybupropion to bupropion by 63% (90% CI, 38–92%; P < 0.01). Conclusion  Baicalin significantly induced CYP2B6-catalyzed bupropion hydroxylation, and the effects of baicalin on other CYP2B6 substrate drugs deserve further investigation.     

Terbinafine increases the plasma concentration of paroxetine after a single oral administration of paroxetine in healthy subjects

Objective Paroxetine is believed to be a substrate of CYP2D6. However, no information was available indicating drug interaction between paroxetine and inhibitors of CYP2D6. The aim of this study was to examine the effects of terbinafine, a potent inhibitor of CYP2D6, on pharmacokinetics of paroxetine. Methods Two 6-day courses of either a daily 150-mg of terbinafine or a placebo, with at least a 4-week washout period, were conducted. Twelve volunteers took a single oral 20-mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 h after dosing. Results Compared with the placebo, terbinafine treatment significantly increased the peak plasma concentration (C_max) of paroxetine, by 1.9-fold (6.4 ± 2.4 versus 12.1 ± 2.9 ng/ml, p < 0.001), and the area under the plasma concentration-time curve from zero to 48 h [AUC (0–48)] of paroxetine by 2.5-fold (127 ± 67 vs 318 ± 102 ng/ml, p < 0.001). Elimination half-life differed significantly (15.3 ± 2.4 vs 22.7 ± 8.8 h, p < 0.05), although the magnitude of alteration (1.4-fold) was smaller than C_max or AUC. Conclusion The present study demonstrated that the metabolism of paroxetine after a single oral dose was inhibited by terbinafine, suggesting that inhibition of CYP2D6 activity may lead to a change in the pharmacokinetics of paroxetine. However, further study is required to confirm this phenomenon at steady state.     

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Statins exert anti-inflammatory effects and downregulate matrix metalloproteinases (MMPs) expression, thus contributing to restore cardiovascular homeostasis in cardiovascular diseases. We aimed at comparing the effects of different statins (simvastatin, atorvastatin, and pravastatin) on MMP-2, MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios released by human umbilical vein endothelial cells (HUVEC) stimulated by phorbol myristate acetate (PMA). HUVECs were incubated with statins (0.1–10 μM) for 12 h before stimulation with PMA 100 nM. Monolayers were used to perform cell viability assays and the supernatants were collected to determine MMPs and TIMPs levels by gelatin zymography and/or enzyme immunoassay. While treatment with PMA increased MMP-9 and TIMP-1 levels (by 556% and 159%, respectively; both P < 0.05), it exerted no effects on MMP-2 and TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, attenuated PMA-induced increases in MMP-9 levels (P < 0.05). Only atorvastatin decreased baseline MMP-2 levels significantly (P < 0.05). We found no effects on TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, decreased MMP-9/TIMP-1 ratio significantly (both P < 0.05), whereas atorvastatin and pravastatin, but not simvastatin, decreased MMP-2/TIMP-2 ratio significantly (both P < 0.05). Our data support the notion that statins with different physicochemical features exert variable effects on MMP/TIMP ratios (which reflect net MMP activity). Our results suggest that more lipophilic statins (simvastatin and atorvastatin), but not the hydrophilic statin pravastatin, downregulate net MMP-9 activity. However, atorvastatin and pravastatin may downregulate net MMP-2 activity. The clinical implications of the present findings deserve further investigation.     

Contribution of age,body weight,and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients

Objective The objective of this study was to assess the contribution of the VKORC1 and CYP2C9 genotypes and age, body size, and weight of the patients to the warfarin dose requirement in a Chinese population. Methods Blood samples were collected from 178 Chinese patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range (1.5–3.0). The polymorphisms for the VKORC1 (-1639GA) and CYP2C9*3 genotypes, venous INR, and plasma concentration and unbound concentration of warfarin were then analyzed. Results VKORC1 (-1639G>A) genotyping showed that 149 patients were homozygous AA, 28 were heterozygous GA, and one was homozygous for the GG genotype. CYP2C9*3 genotyping showed that 162 patients were *1/*1, and 16 patients were heterozygous *1/*3. Patients with the VKORC1(-1639 GG+GA) (3.32 ± 1.02 mg/day) and CYP2C9*1/*1 (2.06 ± 0.82 mg/day) genotypes required a significantly higher warfarin dose than those with the -1639 AA (1.76 ± 0.57 mg/day; P < 0.001) or CYP2C9*1/*3 (1.60 ± 1.29 mg/day; P < 0.001), genotype. The multiple linear regression model for warfarin dose indicated significant contributions from age (r ² = 0.084; P < 0.001), weight (r ² = 0.063; P < 0.001), VKORC1 genotype (r ² = 0.494; P < 0.001), and age, weight, and CYP2C9 and VKORC1 genotype together (r ² = 0.628; P < 0.001). Conclusion This study shows that age, weight and the VKORC1 and CYP2C9 polymorphism affect warfarin dose requirements in our sample of Chinese patients receiving long-term therapy and showing stable control of anticoagulation. It is anticipated that the use of dosing regimens modified by taking into account the contribution of age, weight, and the CYP2C9 and VKORC1 genotypes has the potential to improve the safety of warfarin therapy.     

Clinical efficacy, safety and pharmacokinetics of a newly developed controlled release morphine sulphate suppository in patients with cancer pain

Objective: To compare the efficacy, safety and pharmacokinetics of a newly developed controlled- release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain. Methods: In a double-blind, randomised, two-way cross-over trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration–time curve (AUC)_0–12 h, peak plasma concentration (C_max), time to reach C_max (t_max), and C0 and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0–10 scale, while side effects and rescue medication were recorded. Results: Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC_0–12 h, t_max and C_max of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC_0–12 h and C_max of M6G, and AUC_0–12 h, C_max, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the t_max of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P=0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed. Conclusion: The newly developed controlled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain. Received: 3 September 1999 / Accepted: 15 March 2000     

Voriconazole and fluconazole increase the exposure to oral diazepam

Objective We assessed the effect of voriconazole and fluconazole on the pharmacokinetics and pharmacodynamics of diazepam. Methods Twelve healthy volunteers took 5 mg of oral diazepam in a randomised order on three study sessions: without pretreatment, after oral voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after oral fluconazole 400 mg on the first day and 200 mg on the second day. Plasma concentrations of diazepam and N-desmethyldiazepam were determined for up to 48 h. Pharmacodynamic variables were measured for 12 h. Results In the voriconazole phase, the area under the plasma concentration time curve of diazepam was increased (geometric mean ratio) 2.2-fold (p < 0.05; 90% confidence interval [CI] 1.56 to 2.82). This was associated with the prolongation of the mean elimination half-life (t_1/2) from 31 h to 61 h (p < 0.01) after voriconazole. In the fluconazole phase, the of diazepam was increased 2.5-fold (p < 0.01; 90% CI 1.94 to 3.40), and the t_1/2 was prolonged from 31 h to 73 h (p < 0.001). The peak plasma concentration of diazepam was practically unchanged by voriconazole and fluconazole. The pharmacodynamics of diazepam were changed only modestly. Conclusion Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly.