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Background: Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates.Objective: This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail.Methods: In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim®. The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (Cmax), and trough concentrations for multiple dosings (Ctrough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens.Results: The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate Cmax ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate Cmax ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to < 5-6 mg/L for Ctrough, while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model.Conclusions: Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies. [ABSTRACT FROM AUTHOR]

Purpose: Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine.Methods: Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2-5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg.Results: Voriconazole greatly increased the mean area under the plasma concentration-time curve (AUC0-18) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (Cmax) (3.9-fold), half-life (P < 0.05), and excretion into urine (Ae; P < 0.001). Voriconazole also markedly enhanced the Cmax (P < 0.001), AUC0-18 (P < 0.001), and Ae (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases.Conclusions: Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. Methods: We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured. Results: Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P < 0.001), its peak concentration (C) 1.37-fold ( P < 0.013) and half-life ( t ) 1.37-fold ( P < 0.001). Posaconazole increased the AUC0 of buprenorphine 1.25-fold ( P < 0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05 ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18-2.12; P < 0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases. Conclusions: Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance. [ABSTRACT FROM AUTHOR]

Background: Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-desmethyltramadol (M1), which is mainly accountable for the μ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor). Methods: We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods. Results: Terbinafine increased the area under plasma concentration-time curve (AUC) of tramadol by 115 % and decreased the AUC of M1 by 64 % ( P < 0.001). Terbinafine increased the peak concentration ( C) of tramadol by 53 % ( P < 0.001) and decreased the C of M1 by 79 % ( P < 0.001). After terbinafine pretreatment the elimination half-life of tramadol and M1 were increased by 48 and 50 %, respectively ( P < 0.001). Terbinafine reduced subjective drug effect of tramadol ( P < 0.001). Itraconazole had minor effects on tramadol pharmacokinetics. Conclusions: Terbinafine may reduce the opioid effect of tramadol and increase the risk of its monoaminergic adverse effects. Itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess the effect of withdrawal from the long-term use of temazepam, zopiclone or zolpidem as hypnotics drugs (here referred to as BZD) on cognitive performance. Methods: Ninety-two adults (age ≥55 years) with primary insomnia and who were long-term daily users of BZD volunteered to participate in a 1-month medically supported withdrawal attempt from BZD use, with a subsequent 5-month follow-up. Withdrawal was based on plasma BZD measurements at baseline, at 1 month and during subsequent regular clinical appointments. Attention and psychomotor performance were measured using the CogniSpeed® at baseline and at 1, 2 and 6 months. Reaction times were determined in the Simple Reaction Time (SRT), Two-Choice Reaction Time (2-CRT) and Vigilance tests, and errors were measured by the 2-CRT and Vigilance tests. The cognition data of the withdrawal group were also compared with a cohort of BZD non-users. Results: Eighty-nine (97 %) participants (59 women, 30 men) were followed-up for a maximum of 6 months. During the follow-up period, changes in reaction times and errors did not differ between short-term withdrawers (no residual BZD at 1 month; N = 69), non-withdrawers (residual BZD at 1 month; N = 20) or long-term withdrawers ( N = 34). Compared to the reaction times of the BZD-free cohort, those of BZD users were slower at baseline. The reaction times of BZD withdrawers based on the results of the SRT or 2-CRT tests during follow-up did not reach those of the BZD-free cohort, but there was no difference between these groups in the Vigilance test. Conclusions: Long-term use of BDZ as hypnotic drugs by older adults is related to prolonged impairment of attentional and psychomotor cognitive functioning that persists for at least 6 months after withdrawal. [ABSTRACT FROM AUTHOR]

Background: Accurate predictions of cytochrome P450 (CYP) 3A-mediated drug-drug interactions (DDIs) account for dynamic changes of CYP3A activity at both major expression sites (liver and gut wall) by considering the full pharmacokinetic profile of the perpetrator and the substrate. Physiological-based in vitro-in vivo extrapolation models have become of increasing interest. However, due to discrepancies between the predicted and observed magnitude of DDIs, the role of models fully based on in vivo data is still essential. Objective: The primary objective of this study was to develop a coupled dynamic model for the interaction of the CYP3A inhibitor voriconazole and the prototypical CYP3A substrate midazolam. Methods: Raw concentration data were obtained from a DDI study. Ten subjects were given either no pretreatment (control) or voriconazole twice daily orally. Midazolam was given either intravenously or orally after the last voriconazole dose and during control phases. Data analysis was performed by the population pharmacokinetic approach using non-linear mixed effects modelling (NONMEM 7.2.0). Model evaluation was performed using visual predictive checks and bootstrap analysis. Results: A semiphysiological model was able to describe the pharmacokinetics of midazolam, its major metabolite and voriconazole simultaneously. By considering the temporal disposition of all three substances in the liver and gut wall, a time-varying CYP3A inhibition process was implemented. Only the incorporation of hypothetical enzyme site compartments resulted in an adequate fit, suggesting a sustained inhibitory effect through accumulation. Novel key features of this analysis are the identification of (1) an apparent sustained inhibitory effect by voriconazole due to a proposed quasi accumulation at the enzyme site, (2) a significantly reduced inhibitory potency of intravenous voriconazole for oral substrates, (3) voriconazole as a likely uridine diphosphate glucuronosyltransferase (UGT) 2B inhibitor and (4) considerable sources of interindividual variability. Conclusion: The proposed semiphysiological modelling approach generated a mechanistic description of the complex DDI occurring at major CYP3A expression sites and thus may serve as a powerful tool to maximise information acquired from clinical DDI studies. The model has been shown to draw precise and accurate predictions. Therefore, simulations based on this kind of models may be used for various clinical scenarios to improve pharmacotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Tramadol is mainly metabolized by the cytochrome P450 (CYP) 2D6, CYP2B6 and CYP3A4 enzymes. The aim of this study was to evaluate the effect of enzyme induction with rifampicin on the pharmacokinetics and pharmacodynamics of oral and intravenous tramadol. Methods: This was a randomized placebo-controlled crossover study design with 12 healthy subjects. After pretreatment for 5 days with rifampicin (600 mg once daily) or placebo, subjects were given tramadol either 50 mg intravenously or 100 mg orally. Plasma concentrations of tramadol and its active main metabolite O-desmethyltramadol (M1) were determined over 48 h. Analgesic and behavioral effects and whole blood 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured. Results: Rifampicin reduced the mean area under the time-concentration curve (AUC) of intravenously administered tramadol by 43 % and that of M1 by 58 % ( P < 0.001); it reduced the AUC of oral tramadol by 59 % and that of M1 by 54 % ( P < 0.001). Rifampicin increased the clearance of intravenous tramadol by 67 % ( P < 0.001). Bioavailability of oral tramadol was reduced by rifampicin from 66 to 49 % ( P = 0.002). The pharmacological effects of tramadol or whole blood serotonin concentrations were not influenced by pretreatment with rifampicin. Conclusions: Rifampicin markedly decreased the exposure to tramadol and M1 after both oral and intravenous administration. Therefore, rifampicin and other potent enzyme inducers may have a clinically important interaction with tramadol regardless of the route of its administration. [ABSTRACT FROM AUTHOR]

Purpose: We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. Methods: In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively. Results: Ticlopidine increased the mean area under the plasma concentration-time curve (AUC) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and C by 1.4-fold ( p < 0.001), and reduced its oral and renal clearance ( p < 0.01). Ticlopidine reduced the AUC of M1 ( p < 0.001) and the ratio of the AUC of M1 to that of tramadol, but did not influence the AUC of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases. Conclusions: Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used. [ABSTRACT FROM AUTHOR]

Purpose: We examined the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral S-ketamine. Methods: A randomized crossover open-label study design with two phases at an interval of 4 weeks was conducted in 12 healthy volunteers. Grapefruit juice or water was ingested 200 ml t.i.d. for 5 days. An oral dose of 0.2 mg/kg of S-ketamine was ingested on day 5 with 150 ml grapefruit juice or water. Plasma concentrations of ketamine and norketamine were determined for 24 h, and pharmacodynamic variables were recorded for 12 h. Noncompartmental methods were used to calculate pharmacokinetic parameters. Results: Grapefruit juice increased the geometric mean value of the area under the plasma ketamine concentration-time curve (AUC) by 3.0-fold (range 2.4- to 3.6-fold; P < 0.001), the peak plasma concentration (C) by 2.1-fold (range 1.8- to 2.6-fold; P < 0.001), and the elimination half-life by 24% ( P < 0.05) as compared to the water phase. The ratio of main metabolite norketamine to ketamine (AUC/AUC) was decreased by 57% ( P < 0.001) during the grapefruit phase. Self-rated relaxation was decreased ( P < 0.05) and the performance in the digit symbol substitution test was increased ( P < 0.05) after grapefruit juice, but other behavioral or analgesic effects were not affected. Conclusions: Grapefruit juice significantly increased the plasma concentrations of oral ketamine in healthy volunteers. Dose reductions of ketamine should be considered when using oral ketamine concomitantly with grapefruit juice. [ABSTRACT FROM AUTHOR]

Purpose: Zafirlukast is a substrate of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 3A4 (CYP3A4) in vitro, but the role of these enzymes in its metabolism in vivo is unknown. To investigate the contribution of CYP2C9 and CYP3A4 to zafirlukast metabolism, we studied the effects of fluconazole and itraconazole on its pharmacokinetics (PK). Methods: In a randomized crossover study, 12 healthy volunteers ingested fluconazole 200 mg (first dose 400 mg) once daily, itraconazole 100 mg (first dose 200 mg) twice daily, or placebo twice daily for 5 days, and on day 3, 20 mg zafirlukast. Plasma concentrations of zafirlukast and the antimycotics were measured up to 72 h. Results: Fluconazole increased the total area under the plasma concentration-time curve (AUC) of zafirlukast 1.6-fold [95% confidence interval (CI) 1.3-2.0-fold, P < 0.001), and its peak plasma concentration 1.5-fold (95% CI 1.2-2.0-fold, P < 0.05). Fluconazole did not affect the time of peak plasma concentration or elimination half-life of zafirlukast. None of the zafirlukast PK variables differed significantly from the control in the itraconazole phase; e.g., the ratio to control of the total AUC of zafirlukast was 1.0 (95% CI 0.82-1.2) during the itraconazole phase. Conclusion s: Fluconazole, but not itraconazole, increases zafirlukast plasma concentrations, strongly suggesting that CYP2C9 but not CYP3A4 participates in zafirlukast metabolism in humans. [ABSTRACT FROM AUTHOR]

Purpose: To investigate possible effects of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid (UDCA) and its metabolites in healthy volunteers. Methods: In a crossover study with two phases, 15 healthy volunteers with the SLCO1B1* 1A/* 1A genotype, seven with the * 1B/* 1B genotype, and five with the * 15/* 15 or * 5/* 15 genotype ingested placebo or a single 150-mg dose of UDCA. Plasma concentrations of bile acids and their biosynthesis marker were determined up to 24 h post-ingestion by liquid chromatography-tandem mass spectrometry. Results: The SLCO1B1 genotype had no significant effect on the pharmacokinetics of UDCA. The geometric mean ratios (95% confidence interval) of UDCA area under the plasma concentration-time curve from 0 to 12 h (AUC) in subjects with the SLCO1B1* 1B/* 1B genotype and in subjects with the SLCO1B1* 15/* 15 or * 5/* 15 genotype to the AUC in subjects with the SLCO1B1* 1A/* 1A genotype were 1.07 (0.85, 1.35; P = 0.459) and 0.93 (0.75, 1.15; P = 0.563), respectively. In addition, following either placebo or UDCA administration, the SLCO1B1 polymorphism showed no association with the AUC of the glycine and taurine conjugates of UDCA, with endogenous bile acids, or with the incremental AUC of a bile acid synthesis marker. Compared with placebo, UDCA ingestion increased the AUC of cholic acid, glycochenodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid by 1.5-, 1.1-, 1.2-, and 1.2- fold ( P < 0.05), respectively. Conclusions: Genetic polymorphism in SLCO1B1 does not affect pharmacokinetics of UDCA, suggesting that OATP1B1 is not rate-limiting to the hepatic uptake of therapeutic UDCA. Further studies are required to clarify the mechanisms by which UDCA increases the plasma concentrations of endogenous bile acids. [ABSTRACT FROM AUTHOR]

Purpose: Gemfibrozil, a strong inhibitor of cytochrome P450 (CYP) 2C8 in vivo, was recently found to markedly increase the plasma concentrations of montelukast in humans. Like montelukast, zafirlukast is a substrate of CYP2C9 and CYP3A4 and a potent inhibitor of CYP2C8 in vitro. To investigate the contribution of CYP2C8 to the metabolism of zafirlukast in vivo, we studied the effect of gemfibrozil on the pharmacokinetics of zafirlukast. Methods: Ten healthy subjects in a randomized cross-over study took gemfibrozil 600 mg or placebo twice daily for 5 days, and on day 3, a single oral dose of 20 mg zafirlukast. The plasma concentrations of zafirlukast were measured for 72 h postdose. Results: The mean total area under the plasma concentration-time curve of zafirlukast during the gemfibrozil phase was 102% (geometric mean ratio; 95% confidence interval 89-116%) of that during the placebo phase. Furthermore, there were no statistically significant differences in the peak plasma concentration, time of peak concentration, or elimination half-life of zafirlukast between the phases. Conclusions: Gemfibrozil has no effect on the pharmacokinetics of zafirlukast, indicating that CYP2C8 does not play a significant role in the elimination of zafirlukast. [ABSTRACT FROM AUTHOR]

Background and Objective: Oxycodone is a widely used opioid analgesic, the global use of which has increased several-fold during the last decade. This study was designed to determine the effect of age on the pharmacokinetics of intravenous oxycodone, with special reference to renal function in elderly patients. Methods: We compared the pharmacokinetics of 5 mg of intravenous oxycodone in four groups of 10-11 patients, aged 20-40, 60-70, 70-90 years, undergoing orthopaedic surgery. Plasma concentrations of oxycodone and its noroxycodone, oxymorphone and noroxymorphone metabolites were measured for 24 hours with a liquid chromatography-tandem mass spectrometric method. The cytochrome P450 (CYP) 2D6 genotype of the patients was determined. Glomerular filtration rate (GFR) was estimated on the basis of the age, sex and serum creatinine concentration of the patient. Results: The pharmacokinetics of oxycodone showed age dependency. In the oldest group, the mean area under the plasma concentration-time curve from time zero to infinity (AUC∞) of oxycodone was 80% greater (p < 0.001) and the apparent total body clearance of the drug from plasma (CL) was 34% lower (p < 0.05) than in the youngest group. The mean AUC∞ of oxycodone was also 30-41% greater in the oldest group than in the age groups of 60-70 and 70-80 years (p<0.05). Oxycodone plasma concentrations from 8 hours post-dose were >2-fold higher (p < 0.01) in patients aged >80 years than in patients aged 20-40 years. Noroxycodone AUC∞ was increased in the oldest group compared with patients aged 20-40 and 60-70 years (p < 0.05). There were no significant sex-related, differences in any of the pharmacokinetic parameters. Because 37 of the 41 patients were extensive metabolizers through CYP2D6, the effect of the CYP2D6 genotype on oxycodone pharmacokinetics could not be properly assessed. There was a linear correlation between GFR and CL (p < 0.01, coefficient of determination [r²] = 0.26), volume of distribution at steady state (p<0.05, r² = 0.19) and AUC∞ (p < 0.01, r² = 0.29) of oxycodone. Conclusions: Age is an important factor affecting the pharmacokinetics of oxycodone. Following intravenous administration of oxycodone, patients aged >70 years are expected to have, on average, 40-80% higher exposure to oxycodone than young adult patients. Because oxycodone pharmacokinetics are greatly dependent on the age of the patient, it is important to titrate the analgesic dose individually, particularly in the elderly [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain. Methods: A randomized crossover study design with three phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg, or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioral effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis. Results: Ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-fold (range 1.9- to 4.3-fold; P <0.001) and 2.6-fold (range 1.9- to 3.3-fold; P <0.001). The mean (± SD) elimination half-life increased after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h ( P <0.001) and 5.7 ± 0.9 h ( P <0.001), respectively. Both ritonavir ( P <0.001) and lopinavir/ritonavir ( P <0.05) increased the self-reported drug effect of oxycodone. Conclusions: Ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse effects. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the possible effects of ABCB1 haplotypes on the pharmacokinetics and renin-inhibiting effect of aliskiren. Eleven healthy volunteers homozygous for the ABCB1 c.1236C-c.2677G-c.3435C (CGC) haplotype and 11 homozygous for the c.1236T-c.2677T-c.3435T (TTT) haplotype ingested a single 150-mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h, its excretion into urine up to 12 h, and plasma renin activity up to 24 h. The ABCB1 haplotypes had no significant effect on the pharmacokinetics or renin-inhibiting effect of aliskiren. The geometric mean ratio (95% confidence interval) of aliskiren peak plasma concentration and area under the plasma concentration–time curve from 0 h to infinity in participants homozygous for the TTT haplotype to those in participants homozygous for the CGC haplotype were 1.14 (0.66, 1.96; P = 0.631) and 1.01 (0.58, 1.76; P = 0.960) respectively. These data suggest that the ABCB1 c.1236C-c.2677G-c.3435C and c.1236T-c.2677T-c.3435T haplotypes have no clinically meaningful effect on the pharmacokinetics of aliskiren. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of rifampicin, an inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics and pharmacodynamics of aliskiren, a renin inhibitor used in the treatment of hypertension. In a randomized crossover study, 12 healthy volunteers took 600 mg rifampicin or placebo once daily for 5 days. On day 6, they ingested a single 150-mg dose of aliskiren. Plasma aliskiren concentrations were measured up to 72 h and urine concentrations up to 12 h; pharmacodynamic variables were measured up to 24 h. Rifampicin reduced the peak plasma aliskiren concentration (Cmax) by 39% (95% confidence interval 0.41, 0.90; P = 0.017) and the area under the plasma aliskiren concentration–time curve $$ \left( {{\hbox{AU}}{{\hbox{C}}_{0 - \infty }}} \right) $$ by 56% (95% confidence interval 0.35, 0.56; P < 0.001). Rifampicin had no significant effect on aliskiren elimination half-life (t½) or its renal clearance (Clrenal). Plasma renin activity 24 h after aliskiren intake was 61% higher during the rifampicin phase than during the placebo phase ( P = 0.008). Rifampicin considerably reduces the plasma concentrations and the renin-inhibiting effect of aliskiren by decreasing its oral bioavailability. [ABSTRACT FROM AUTHOR]

The 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. Twelve 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. Itraconazole 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. Itraconazole 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. [ABSTRACT FROM AUTHOR]

We investigated the effect of voriconazole on the pharmacokinetics and pharmacodynamics of oxycodone. Twelve healthy subjects ingested either voriconazole or placebo for 4 days in a randomized, cross-over study. On day 3, they ingested 10 mg oxycodone. Timed plasma samples were collected for the measurement of oxycodone, noroxycodone, oxymorphone, noroxymorphone and voriconazole up to 48 h, and pharmacodynamic effects were recorded. When voriconazole was taken at the same time as oxycodone, the mean area under the plasma concentration-time curve (AUC0–∞) of oxycodone increased 3.6-fold (range 2.7- to 5.6-fold), peak plasma concentration 1.7-fold and elimination half-life 2.0-fold ( p < 0.001) when compared to placebo. The AUC0-∞ ratio of noroxycodone to oxycodone was decreased by 92% ( p < 0.001), and that of oxymorphone increased by 108% ( p < 0.01). Pharmacodynamic effects of oxycodone were modestly increased by voriconazole. Voriconazole inhibits the CYP3A-mediated N-demethylation of oxycodone, drastically increasing exposure to oral oxycodone. Clinically, lower doses of oxycodone may be needed during voriconazole treatment to avoid opioid-related adverse effects especially after repeated dosing. [ABSTRACT FROM AUTHOR]

The effect of topical miconazole oral gel and systemic oral voriconazole on the pharmacokinetics of oral etoricoxib was studied in 12 healthy volunteers. Plasma concentrations of etoricoxib, miconazole, voriconazole, and thromboxane B2 generation were followed after ingestion of 60 mg etoricoxib without pretreatment, after topical administration of miconazole oral gel (85 mg × 3, 3 days), or after oral voriconazole (400 mg × 2, 1st day, 200 mg × 2, 2nd day). Etoricoxib area under the plasma concentration-time curve $$\left( {{\text{AUC}}_{0 - \infty } } \right)$$ and maximum plasma concentration (Cmax) geometric mean ratios (GMR) with/without miconazole were 1.69 {90% confidence interval (CI); 1.46–1.92} and 1.12 (90% CI; 0.99–1.25), respectively, and corresponding GMRs with/without voriconazole were 1.49 (90% CI; 1.37–1.61) and 1.19 (90% CI; 1.08–1.31), respectively. Miconazole oral gel and oral voriconazole produced comparable increase in the exposure to etoricoxib, presumably via CYP3A inhibition. [ABSTRACT FROM AUTHOR]

We recently discovered that rofecoxib is a potent mechanism-based inhibitor of CYP1A2. The effect of the widely used cyclo-oxygenase-2 selective non-steroidal anti-inflammatory drug celecoxib on CYP1A2 activity has not been reported. The effect of celecoxib on CYP1A2 activity (phenacetin O-deethylation) was first studied in vitro using human liver microsomes. This was followed by a randomized, placebo-controlled, cross-over study in which 12 healthy volunteers were given celecoxib (200 mg twice daily) or placebo for 4 days. On day 3, a caffeine test was performed. On day 4, the subjects ingested 2 mg tizanidine. Plasma samples for the measurement of the concentrations of tizanidine, its metabolites and celecoxib were collected up to 24 h post-administration. Pharmacodynamic variables (e.g. blood pressure, subjective drowsiness and drug effect) were recorded up to 12 h post-adm. Celecoxib was found to be a moderately potent competitive inhibitor of CYP1A2 in vitro with a Ki (inhibitor constant) of 25.4 μ M. However, in vivo, celecoxib did not affect the caffeine test, or the peak concentration, time to peak concentration, area under the concentration-time curve or half-life of tizanidine. The pharmacodynamic variables of tizanidine also remained unchanged. Unlike rofecoxib, celecoxib does not clinically to significantly inhibit CYP1A2. The lack of significant in vivo inhibition of CYP1A2 can be correctly predicted on the basis of in vitro Ki data and the free peripheral or portal plasma concentration of celecoxib. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

We studied the effects of gender and smoking on the pharmacokinetics and effects of the cytochrome P450 (CYP) 1A2 substrate tizanidine. Seventy-one healthy young volunteers (male and female nonsmokers, male smokers) ingested 4 mg tizanidine. Plasma concentrations and pharmacodynamics of tizanidine were measured, and a caffeine test was performed. Among nonsmokers, the peak concentration (Cmax) and area under concentration-time curve from 0 to infinity [AUC(0-∞)] of tizanidine did not differ significantly between females and males. However, the half-life (t1/2) was 9% shorter in female nonsmokers than in male nonsmokers ( P < 0.05). In male smokers, the t1/2 was 10% shorter and the weight-adjusted AUC(0-∞) 33% smaller than in male nonsmokers ( P < 0.05). The caffeine/paraxanthine ratio was 35–40% smaller ( P = 0.001) in male smokers than in nonsmoking males or females, but did not differ between males and females. Tizanidine lowered blood pressure and caused drowsiness significantly ( P < 0.05) more in females than in either male groups. The effects on blood pressure were smallest in male smokers ( P < 0.05). Gender by itself seems to have no clinically significant effect on the pharmacokinetics of tizanidine, whereas smoking reduces plasma concentrations and effects of tizanidine. Any possible effect of gender and smoking is largely outweighed by individual variability in CYP1A2 activity due to genetic and environmental factors and in body weight. Careful dosing of tizanidine is warranted in small females, whereas male smokers can require higher than average doses. [ABSTRACT FROM AUTHOR]

We assessed the effect of voriconazole and fluconazole on the pharmacokinetics and pharmacodynamics of diazepam. 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. In the voriconazole phase, the area under the plasma concentration time curve $$ {\left( {{\text{AUC}}_{{{\text{0 - }}\infty }} } \right)} $$ 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 (t1/2) from 31 h to 61 h ( p < 0.01) after voriconazole. In the fluconazole phase, the $$ {\text{AUC}}_{{{\text{0 - }}\infty }} $$ of diazepam was increased 2.5-fold ( p < 0.01; 90% CI 1.94 to 3.40), and the t1/2 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. 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. [ABSTRACT FROM AUTHOR]

Our aim was to correlate the in vitro and in vivo CYP1A2 inhibition potential of tolfenamic acid, an NSAID highly (99.7%) bound to plasma proteins, to study the significance of protein binding of inhibitor in metabolic drug interactions. The effect of tolfenamic acid on CYP1A2 (phenacetin O-deethylation) was studied using human liver microsomes, with and without albumin (0–10 mg/ml). In a randomized, crossover study, 10 volunteers took 200 mg tolfenamic acid or placebo t.i.d. for 3 days. On day 2, a caffeine test was performed. On day 3, each ingested 4 mg of the CYP1A2 substrate tizanidine. Plasma tizanidine, its metabolites (M) and tolfenamic acid, and pharmacodynamic variables were measured. Tolfenamic acid strongly inhibited phenacetin-O-deethylation in vitro (IC50 1.8 μM without albumin). Albumin decreased its inhibitory effect in a concentration-dependent manner; the IC50 exceeded 100 μM with 10 mg/ml of albumin. Tolfenamic acid had no effect on the area under the concentration-time curve $${\left( {{\text{AUC}}_{{0 - \infty }} } \right)}$$ , peak concentration, time of peak concentration or half-life of tizanidine or M-3; only the $${\text{AUC}}_{{0 - \infty }} $$ of secondary metabolite M-4 was slightly decreased (13%, P = 0.004). The caffeine test and the pharmacodynamic effects of tizanidine were unchanged. Tolfenamic acid potently inhibits CYP1A2 in vitro when studied without albumin, but not in vivo. This apparent discrepancy is due to the high protein binding of tolfenamic acid. To avoid overestimation of the interaction potential, the inhibitory effect of highly albumin-bound compounds should also be studied in vitro with albumin, or their exact unbound plasma concentration should be used in predictions. [ABSTRACT FROM AUTHOR]

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. 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. Gemfibrozil raised the mean total area under the plasma concentration-time curve (AUC0–∞) 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 AUC0–∞ ratio of R-ibuprofen to S-ibuprofen was increased by gemfibrozil ( P < 0.001). Gemfibrozil moderately increases the AUC0–∞ 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. [ABSTRACT FROM AUTHOR]

Objective: Zopiclone is a short acting hypnotic, which is metabolised by cytochrome P450 (CYP) 3A4 and 2C8 in vitro. We studied the possible effect of gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics and pharmacodynamics of zopiclone. Methods: In a randomised 2-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each ingested a 7.5 mg dose of zopiclone. Plasma concentrations and urinary excretion of zopiclone and its two primary metabolites, plasma gemfibrozil, and psychomotor performance were measured. The effects of CYP2C8, CYP2C9 and CYP3A4 inhibitors on the depletion of zopiclone (500 nM) were studied in vitro in human liver microsomes. Results: The pharmacokinetic variables of the parent zopiclone were not significantly affected by gemfibrozil. However, gemfibrozil raised the mean peak plasma concentration (Cmax) of N-oxide-zopiclone (1.6-fold; P<0.001) and that of N-desmethylzopiclone (1.2-fold; P<0.001). The mean area under the plasma concentration-time curve (AUC0-∞) values of N-oxide-zopiclone and N-desmethyl-zopiclone were raised 2-fold (P<0.001) and 1.2-fold (P<0.01), respectively. The renal clearance of N-oxide-zopiclone was reduced by 48% by gemfibrozil (P<0.001). The pharmacodynamic effects of zopiclone, measured using psychometric tests, were not affected by gemfibrozil. In vitro, ketoconazole (1 μM) and itraconazole (8 μM) decreased the elimination rate of zopiclone enantiomers by about 65–95%, while montelukast (16 μM), gemfibrozil (200 μM) and sulfaphenazole (10 μM) had no appreciable effect. Conclusions: Gemfibrozil does not increase the plasma concentrations of the parent zopiclone. Accordingly, CYP2C8 does not significantly metabolise zopiclone in vivo. However, as gemfibrozil raises the concentrations of two potentially active metabolites of zopiclone, slightly enhanced effects of zopiclone by gemfibrozil can not be excluded. [ABSTRACT FROM AUTHOR]

Objective: Pioglitazone, a thiazolidinedione antidiabetic drug, is metabolised mainly by the cytochrome P450 (CYP) 2C8 enzyme. The leukotriene receptor antagonists montelukast and zafirlukast have potently inhibited CYP2C8 activity and the metabolism of pioglitazone in vitro. Our objective was to determine whether montelukast and zafirlukast increase the plasma concentrations of pioglitazone in humans. Methods: In a randomised, double-blind crossover study with three phases and a washout period of 3 weeks, 12 healthy volunteers took either 10 mg montelukast once daily and placebo once daily, or 20 mg zafirlukast twice daily, or placebo twice daily, for 6 days. On day 3, they received a single oral dose of 15 mg pioglitazone. The plasma concentrations of pioglitazone and its metabolites M-IV, M-III, M-Vand M-XI were measured for 96 h. Results: The total area under the plasma concentration-time curve of pioglitazone during the montelukast and zafirlukast phases was 101% (range 71-143%) and 103% (range 78-146%), respectively, of that during the placebo phase. Also, the peak plasma concentration and elimination half-life of pioglitazone remained unaffected by montelukast and zafirlukast. There were no statistically significant differences in the pharmacokinetics of any of the metabolites of pioglitazone between the phases. Conclusions: Montelukast and zafirlukast do not increase the plasma concentrations of pioglitazone, indicating that their inhibitory effect on CYP2C8 is negligible in vivo, despite their strong inhibitory effect on CYP2C8 in vitro. The results highlight the importance of in vivo interaction studies and of the incorporation of relevant pharmacokinetic properties of drugs, including plasma protein binding data, to in vitro-in vivo interaction predictions. [ABSTRACT FROM AUTHOR]

Objective: Organic anion transporting polypeptide 1B1 (OATP1B1) is a drug uptake transporter located at the sinusoidal membrane of hepatocytes. Our aim was to establish high-throughput genotyping assays for the major known single nucleotide polymorphisms (SNP) in the SLCO1B1 gene encoding OATP1B1 and to investigate the frequencies of SNPs and haplotypes of SLCO1B1 in a large Caucasian population. Methods: Distribution of SLCO1B1 alleles was determined in 468 healthy Finnish Caucasian subjects at 11 variant sites spanning the entire gene by using allelic discrimination with TaqMan 5′ nuclease assays. Results: The allelic frequencies of SLCO1B1 SNPs were 9.7% for g.-11187G>A, 0.4% for g.-11110T>G, 8.0% for g.-10499A>C, 46.2% for c.388A>G, 13.1% for c.411G>A, 13.1% for c.463C>A, 20.2% for c.521T>C, 53.2% for c.571T>C, 46.4% for c.597C>T, 4.0% for c.1929A>C and 48.8% for c.*439T>G. Altogether, 26 haplotypes were statistically inferred. The most common haplotype, with a frequency of 35.6%, contained variant allele C at position c.571, but had the reference nucleotide at all other positions investigated. The functionally significant c.521T>C SNP existed in four major haplotypes, which could be differentiated by the g.-11187G>A, g.-10499A>C and c.388A>G SNPs. The frequencies of these haplotypes were 7.9% for g.-11187G/g.-10499C/c.388G/c.521C (*16), 6.9% for AAGC (*17), 2.7% for GAAC (*5) and 2.4% for GAGC (*15). Conclusion: Sequence variations of SLCO1B1 occur at high frequencies in the Caucasian population. Further studies are needed to characterise the effects of SLCO1B1 haplotypes, especially *16, *17, *15 and *5, on drug pharmacokinetics and response, and to determine the frequencies of SLCO1B1 SNPs and haplotypes in different populations. [ABSTRACT FROM AUTHOR]

Objective: Loperamide is biotransformed in vitro by the cytochromes P450 (CYP) 2C8 and 3A4 and is a substrate of the P-glycoprotein efflux transporter. Our aim was to investigate the effects of itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, and gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics of loperamide. Methods: In a randomized crossover study with 4 phases, 12 healthy volunteers took 100 mg itraconazole (first dose 200 mg), 600 mg gemfibrozil, both itraconazole and gemfibrozil, or placebo, twice daily for 5 days. On day 3, they ingested a single 4-mg dose of loperamide. Loperamide and N-desmethylloperamide concentrations in plasma were measured for up to 72 h and in urine for up to 48 h. Possible central nervous system effects of loperamide were assessed by the Digit Symbol Substitution Test and by subjective drowsiness. Results: Itraconazole raised the peak plasma loperamide concentration (Cmax) 2.9-fold (range, 1.2.5.0; P<0.001) and the total area under the plasma loperamide concentration-time curve (AUC0-∞) 3.8-fold (1.4.6.6; P<0.001) and prolonged the elimination half-life (t.) of loperamide from 11.9 to 18.7 h (P<0.001). Gemfibrozil raised the Cmax of loperamide 1.6-fold (0.9.3.2; P<0.05) and its AUC0-∞ 2.2-fold (1.0.3.7; P<0.05) and prolonged its t. to 16.7 h (P<0.01). The combination of itraconazole and gemfibrozil raised the Cmax of loperamide 4.2-fold (1.5.8.7; P<0.001) and its AUC0-∞ 12.6-fold (4.3.21.8; P<0.001) and prolonged the t. of loperamide to 36.9 h (P<0.001). The amount of loperamide excreted into urine within 48 h was increased 3.0-fold, 1.4-fold and 5.3-fold by itraconazole, gemfibrozil and their combination, respectively (P<0.05). Itraconazole, gemfibrozil and their combination reduced the plasma AUC0.72 ratio of N-desmethylloperamide to loperamide by 65%, 46% and 88%, respectively (P<0.001). No significant differences were seen in the Digit Symbol Substitution Test or subjective drowsiness between the phases. Conclusion: Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide. Although not seen in the psychomotor tests used, an increased risk of adverse effects should be considered during concomitant use of loperamide with itraconazole, gemfibrozil and especially their combination. [ABSTRACT FROM AUTHOR]

Objective: Rifampicin greatly reduces the plasma concentrations of many drugs. Our aim was to characterise the inducibility of cytochrome P450 (CYP) 1A2 by rifampicin, using tizanidine and caffeine as probe drugs for presystemic and systemic CYP1A2-mediated metabolism. Methods: In a randomised, 2-phase crossover study, ten healthy volunteers were given a 5-day pretreatment with 600 mg rifampicin or placebo once daily. On day 6, a single 4-mg dose of tizanidine was administered orally. Plasma and urine concentrations of parent tizanidine and several of its metabolites (M-3, M-4, M-5, M-9, M-10) and pharmacodynamic variables were measured up to 24 h. A caffeine test was performed in both phases. Results: Rifampicin moderately reduced the peak plasma concentration (by 51%; P=0.002) and area under the plasma concentration-time curve [AUC(0-∞)] (by 54%; P=0.009) of parent tizanidine, and had no effect on its half-life. The tizanidine/M-3 and tizanidine/M-4 AUC(0-∞) ratios were slightly (by 30%; P=0.014; and by 38%; P=0.007) decreased by rifampicin. Also, the excretion of metabolites M-3, M-4 and M-5 into urine was reduced (P<0.005), but that of M-10 was increased (P=0.008) by rifampicin. Rifampicin reduced the tizanidine/M-10 ratio (by 55%; P=0.047) but had no significant effect on the other tizanidine/metabolite ratios in urine. The caffeine/paraxanthine ratio was reduced by 23% (P=0.081) by rifampicin. The effect of rifampicin on the caffeine/paraxanthine ratio correlated significantly with the effect of rifampicin on, for example, the AUC(0-∞) of tizanidine and the tizanidine/M-3 AUC(0-∞) ratio. The pharmacodynamic effects of tizanidine were reduced by rifampicin. Conclusions: Rifampicin moderately decreases the plasma concentrations of tizanidine. The strong inducing effects of rifampicin on other CYP enzymes, e.g. CYP3A4, may have contributed to the findings, and the inducibility of CYP1A2-mediated presystemic (tizanidine) and systemic (tizanidine, caffeine) metabolism by rifampicin is weak at the most. Compared to CYP3A4 substrate drugs, substrates of CYP1A2 are much less susceptible to drug interactions caused by enzyme inducers of the rifampicin type. [ABSTRACT FROM AUTHOR]

Objective: Pioglitazone, a thiazolidinedione anti-diabetic, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4. In patients with type 2 diabetes, the pioglitazone-repaglinide combination has acted synergistically on glycaemic parameters. Our aim was to determine whether pioglitazone increases the plasma concentrations of repaglinide. Methods: In a randomized, 2-phase cross-over study, 12 healthy volunteers received 30 mg pioglitazone or placebo once daily for 5 days. On day 5, they ingested a single 0.25 mg dose of repaglinide 1 h after the last pretreatment dose. Plasma repaglinide and pioglitazone, and blood glucose concentrations were measured for 12 h. Results: During the pioglitazone phase, the mean peak plasma repaglinide concentration (Cmax) and the total area under the concentration-time curve [AUC(0-∞)] of repaglinide were 100% (range 53–157%, P=0.99) and 90% (range 63–120%, P=0.22), respectively, of those during the placebo phase. Also the half-life of repaglinide was unaffected, but the median peak time of repaglinide was shortened from 40 min to 20 min by pioglitazone (P=0.014). The short-term pioglitazone administration did not modify the blood glucose-lowering effect of a single dose of repaglinide. Conclusions: Pioglitazone does not increase the plasma concentrations of repaglinide, indicating that the inhibitory effect of pioglitazone on CYP2C8 and CYP3A4 is very weak in vivo, probably due to its extensive plasma protein binding. The synergistic effect of repaglinide and pioglitazone on the glycaemic parameters, seen in patients with type 2 diabetes during their long-term use, is unlikely to be caused by inhibition of repaglinide metabolism by pioglitazone. [ABSTRACT FROM AUTHOR]

Background: Prescribing drugs to pregnant women requires the balancing of benefits and risks. Only a small proportion of drugs are known to be harmful to the fetus, but for the vast majority of drugs little evidence of fetal safety exists.Aim: To determine the prescription pattern of potentially and clearly harmful prescription drugs during pregnancy with reference to drug safety categorisation, and to define the drug groups primarily responsible for multiple drug use during pregnancy.Study Design: A retrospective, register-based cohort study.Methods: Linkage of three nationwide registers in Finland. Data collection included prescription drugs purchased during the preconception period and each trimester in the pregnant cohort, and the corresponding time periods in the non-pregnant controls. The pregnancy safety categorisation was determined for each drug (Anatomic Therapeutic Chemical [ATC] code) by using the Swedish classification of approved medicinal products (Farmaceutiska Specialiteter i Sverige [FASS]) and if not available, the corresponding Australian (Australian Drug Evaluation Committee [ADEC]) or US categorisation (FDA). GROUPS STUDIED: Women applying for maternity support (maternal grants) during the year 1999 (n = 43 470) plus non-pregnant control women matched by age and hospital district (n = 43 470).Results: In the pregnant cohort, 20.4% of women purchased at least one drug classified as potentially harmful during pregnancy, and 3.4% purchased at least one drug classified as clearly harmful. A significant decline occurred in the number of pregnant women purchasing potentially and clearly harmful drugs during the first trimester when compared with the preconception period, and the decline continued from the first to the second trimester. In the pregnant cohort, 107 (0.2%) women purchased at least ten different drugs during pregnancy. The drugs most commonly purchased in this group were topical corticosteroids and nasal preparations.Conclusion: The use of hazardous prescription drugs declines during pregnancy but prescriptions of known teratogens and the relatively frequent practice of polypharmacy in epilepsy place emphasis on the need for careful pre-pregnancy counselling. However, drug safety classifications give a very crude estimation of risk and should only be used as general guidelines when planning treatment. Risk assessment must always be made on an individual basis, and pregnant women with illnesses requiring treatment must be treated adequately. [ABSTRACT FROM AUTHOR]

The antituberculosis drug rifampicin (rifampin) induces a number of drug-metabolising enzymes, having the greatest effects on the expression of cytochrome P450 (CYP) 3A4 in the liver and in the small intestine. In addition, rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein. Full induction of drug-metabolising enzymes is reached in about 1 week after starting rifampicin treatment and the induction dissipates in roughly 2 weeks after discontinuing rifampicin. Rifampicin has its greatest effects on the pharmacokinetics of orally administered drugs that are metabolised by CYP3A4 and/or are transported by P-glycoprotein. Thus, for example, oral midazolam, triazolam, simvastatin, verapamil and most dihydropyridine calcium channel antagonists are ineffective during rifampicin treatment. The plasma concentrations of several anti-infectives, such as the antimycotics itraconazole and ketoconazole and the HIV protease inhibitors indinavir, nelfinavir and saquinavir, are also greatly reduced by rifampicin. The use of rifampicin with these HIV protease inhibitors is contraindicated to avoid treatment failures. Rifampicin can cause acute transplant rejection in patients treated with immunosuppressive drugs, such as cyclosporin. In addition, rifampicin reduces the plasma concentrations of methadone, leading to symptoms of opioid withdrawal in most patients. Rifampicin also induces CYP2C-mediated metabolism and thus reduces the plasma concentrations of, for example, the CYP2C9 substrate (S)-warfarin and the sulfonylurea antidiabetic drugs. In addition, rifampicin can reduce the plasma concentrations of drugs that are not metabolised (e.g. digoxin) by inducing drug transporters such as P-glycoprotein. Thus, the effects of rifampicin on drug metabolism and transport are broad and of established clinical significance. Potential drug interactions should be considered whenever beginning or discontinuing rifampicin treatment. It is particularly important to remember that the concentrations of many of the other drugs used by the patient will increase when rifampicin is discontinued as the induction starts to wear off. [ABSTRACT FROM AUTHOR]

Objective. To examine the use of prescription drugs in Finnish women before and during pregnancy and lactation. Methods. A register-based study linking four nation-wide registers in Finland: the Maternal Grants Register, the Drug Prescription Register, and the Special Refund Register (all maintained by the Social Insurance Institution in Finland; KELA), and the Finnish Population Register. The study included all women applying for maternity support (maternal grants) during the year 1999, and non-pregnant control women matched by age and hospital district. Data collection included the number and type of prescription drugs purchased by the two cohorts during preconception (3 months before pregnancy), each trimester, and lactation. Results. Of the 43,470 pregnant women, 46.2% purchased at least one drug and 12.7% three or more different drugs during pregnancy. Corresponding proportions for the control cohort were 55.2% (OR 0.7, 95% CI 0.6–0.7) and 23.0% (OR 0.5, 95% CI 0.5–0.5). The drugs most frequently purchased during pregnancy were systemic antibiotics (24.1% of pregnant women vs 27.3% controls; OR 0.8, 95% CI 0.8–0.9) and gynaecological anti-infective agents (8.3% vs 1.5%; OR 5.5, 95% CI 5.5–6.5). For pregnant women, purchases of most drug groups had already declined during the first trimester, but no reduction was apparent in drugs for chronic illnesses (epilepsy, asthma, diabetes). Conclusions. Although drugs were purchased abundantly during pregnancy, a significant decline occurred for most drug groups. The medication pattern for chronic illnesses remained unchanged. The purchase of several different drugs was relatively common and raises concerns. [ABSTRACT FROM AUTHOR]

Objective. To assess the effect of ciprofloxacin on the pharmacokinetics of ropivacaine. Methods. In a double-blind, randomised, cross-over study, nine healthy volunteers were treated for 2.5 days with 500 mg oral ciprofloxacin or placebo twice daily. On day 3, they received a single dose of 0.6 mg/kg ropivacaine intravenously over 30 min. Ropivacaine, 3-hydroxyropivacaine (3-OH-ropivacaine), and (S)-2′,6′-pipecoloxylidide (PPX) in venous plasma and urine were measured for up to 12 h and 24 h, respectively. Results. Ciprofloxacin decreased the mean clearance (CL) of ropivacaine by 31% (P<0.05), with a considerable inter-individual variation (range from -52% to +39%). It also decreased the area under the plasma concentration–time curve (AUC) of 3-OH-ropivacaine by 38% (P<0.05) and urinary excretion of 3-OH-ropivacaine by 27% (P<0.05). Ciprofloxacin increased the AUC of PPX by 71% (P<0.01) and urinary excretion of PPX by 97% (P<0.01). Conclusion. Ciprofloxacin modestly decreased the mean ropivacaine CL by inhibiting the CYP1A2-mediated formation of 3-OH-ropivacaine. At the same time, the CYP3A4-mediated formation of PPX was increased. There was a marked inter-individual variation in the extent of the interaction, and, for some individuals, the concomitant use of ciprofloxacin with ropivacaine might produce toxic symptoms. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of the study was to find out whether there is an association between use of enzyme-inducing antiepileptic medicines and cancer. Methods: A cohort of 14,487 male and 13,932 female patients who received reimbursement for antiepileptic drugs (AEDs) in 1979–1981 in Finland was followed for subsequent cancers up to 1997 through the Finnish Cancer Registry. Results: During the follow-up, 2242 cancer cases were observed, while the expected number based on national incidence rates was 1743. Over 40% of the excess was attributable to cancer of the brain and nervous system [standardised incidence ratio (SIR) 4.30, 95% confidence interval (CI) 3.81, 4.82]. The relative risk of meningiomas was very high (SIR 46.6, 95% CI 22.3, 85.6) only during the first year of reimbursement, while the risk of gliomas remained tenfold or higher for 7 years and was significantly increased for 19 years in patients taking AEDs. Also cancers of the larynx (SIR 1.77), liver (1.71), pancreas (1.35), colon (1.32), stomach (1.30) and lung (1.29) showed statistically increased risks. Conclusion: As epilepsy can be a symptom of cancers of the nervous system, the role of AEDs in their occurrence is speculative albeit possible. The excess of some cancers might be attributable to enzyme-inducing antiepileptic drugs, but the excess is not very high compared with the benefits obtained with these drugs. [ABSTRACT FROM AUTHOR]

Objective: In order to evaluate the inhibitory effects of isoniazid on cytochrome P450 (CYP) mediated drug metabolism, the in vitro inhibitory potency and specificity as well as the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-, time- and concentration dependency of isoniazid as an inhibitor of the activity of the major human CYP isoforms were studied. Methods: Using pooled human liver microsomes, the in vitro inhibitory effects of isoniazid on CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2C19 (S-mephenytoin 4′-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone 6-hydroxylation) and CYP3A4 (midazolam 1'-hydroxylation) activities were examined. Results: After a 15-min preincubation without NADPH, isoniazid reversibly inhibited microsomal CYP2C19- and CYP3A4-mediated reactions with apparent Ki values of 36 µM and 73 µM, respectively. However, isoniazid had only weak inhibitory effects on the five other CYP-mediated reactions (Ki>110 µM). After a 15-min preincubation with NADPH, isoniazid showed an increased inhibitory potency toward CYP1A2, CYP2A6, CYP2C19 and CYP3A4 activities (Ki=56, 60, 10 and 36 µM, respectively). In addition, the inactivation of CYP1A2, CYP2A6, CYP2C19 and CYP3A4 by isoniazid was NADPH-, time- and concentration dependent, and was characterised by Kinact values of 0.11, 0.13, 0.09 and 0.08 min–1, and KI values of 285, 173, 112 and 228 µM, respectively. Conclusions: As the peak plasma concentrations of isoniazid are around 30–50 µM, isoniazid at clinically relevant concentrations reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 in human liver microsomes. Co-administration of isoniazid and drugs that are primarily metabolised by these CYP isoforms, particularly by CYP2C19 and CYP3A4, may result in significant drug interactions. [ABSTRACT FROM AUTHOR]

Objective: To characterise the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of selegiline in healthy volunteers. Methods: In this randomised, placebo-controlled crossover study with two phases, 12 healthy volunteers took either 200 mg itraconazole or matched placebo once daily for 4 days. On day 4, a single 10-mg oral dose of selegiline hydrochloride was administered. Serum concentrations of selegiline and its primary metabolites desmethylselegiline and l-methamphetamine were determined up to 32 h. A caffeine test was performed on day 3 of both phases, by measuring the plasma paraxanthine/caffeine concentration ratio 6 h after caffeine intake, to examine the role of CYP1A2 in selegiline pharmacokinetics. In addition, the effects of itraconazole on the metabolism of selegiline in vitro were characterised by using human liver microsomes. Results: Itraconazole had no significant effects on the pharmacokinetic variables of selegiline, desmethylselegiline or l-methamphetamine, with the exception that the AUC of desmethylselegiline was increased by about 10% (P<0.05). There was a significant correlation between the AUC(desmethylselegiline)/AUC(selegiline) ratio and the paraxanthine/caffeine ratio (r=0.41; P<0.05), suggesting involvement of CYP1A2 in the formation of desmethylselegiline. In experiments with human liver microsomes, itraconazole had no inhibitory effect on the formation of either desmethylselegiline or l-methamphetamine from selegiline. Conclusions: The pharmacokinetics of selegiline in healthy volunteers were unaffected by the potent CYP3A4 inhibitor itraconazole. In addition, itraconazole showed no inhibitory effect on the biotransformation of selegiline to desmethylselegiline and l-methamphetamine by human liver microsomes. These findings suggest that selegiline is not susceptible to interaction with CYP3A4 inhibitors. [ABSTRACT FROM AUTHOR]

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A letter to the editor is presented in response to the article “On the Possible Interaction Between Vaccines and Drugs" by Pellegrino et al. in the May 8, 2014 issue.

A letter to the editor is presented which is concerned with the interaction of oxycodone and voriconazole in a series of patients with cancer pain.