Effect of fluconazole dose on the extent of fluconazole-triazolam interaction

1 Azole antimycotics interact with the short acting hypnotic triazolam. The effect of fluconazole dose on the extent of fluconazole-triazolam interaction was investigated in a double-blind, randomized cross-over study of four phases.
2 Eight healthy volunteers received either 50  mg, 100  mg or 200  mg (400  mg on day 1) of fluconazole or placebo orally once a day for 4 days. On day 4, they took a 0.25  mg oral dose of triazolam, after which plasma samples were collected and pharmacodynamic effects measured for 18  h.
3 The mean area under the triazolam concentration-time curve (AUC) was increased 1.6-, 2.1- and 4.4-fold ( P <0.001) by fluconazole 50  mg, 100  mg and 200  mg, respectively. The increase in the elimination half-life of triazolam ( t _½,z) varied from 1.3-fold (fluconazole 50  mg, P <0.05) to 2.3-fold (fluconazole 200  mg, P <0.001). The peak concentration of triazolam was also increased significantly during all fluconazole phases; more than twofold by fluconazole 200  mg ( P <0.001).
4 The pharmacodynamic effects of triazolam were increased significantly ( P <0.05) by fluconazole 100  mg and 200  mg.
5 Even a small 50  mg daily dose of fluconazole can interact with triazolam and the extent of the interaction increases with increasing fluconazole dose. When triazolam is used concomitantly with fluconazole 50–200  mg, the dose of triazolam should be reduced, accordingly. Simultaneous use of triazolam with higher fluconazole doses should be avoided.     

Effect of twoβ-blockers on stress during mental arithmetic

Heart rate, blood pressure, and subjective stress ratings were recorded from 36 healthy normotensive students at three points in time: during a drug-free baseline, during a baseline 2 h after ingesting single oral doses of atenolol (75 mg), metoprolol (150 mg), or lactate placebo, and during a subsequently administered mental arithmetic test. Both-blockers equally reduced baseline heart rate and heart rate response to arithmetic, but subjective stress rating increases to arithmetic were greater for atenolol than for placebo and metoprolol. These results are contrary to peripheral theories of anxiety regulation. While the hydrophilic atenolol barely penetrates the blood-brain barrier, the lipophilic metoprolol can exert direct CNS effects in addition to its peripheral actions. Central stress-dampening effects of lipophilic-blockers may override peripheral baroreceptor-mediated stress-promoting effects.     

Mucosal interleukin-1β production and acid secretion in enlarged fold gastritis

Background : We have previously shown that eradication of Helicobacter pylori increases acid secretion in H. pylori -associated enlarged fold gastritis.
Aim : To investigate whether locally produced interleukin-1β is possibly involved in the inhibition of acid secretion in H. pylori gastritis.
Methods : IL-1β release from the gastric body mucosa was determined by short-term culture of biopsy specimens in 13 patients with enlarged fold gastritis (all H. pylori -positive), five H. pylori -positive and 10 H. pylori -negative patients without enlarged folds. The acid-inhibitory effect of locally produced IL-1β was examined by [¹⁴C]-aminopyrine uptake assay using isolated rabbit gastric glands.
Results : IL-1β release was significantly greater in patients with enlarged fold gastritis, significantly correlated with both basal and tetragastrin-stimulated acid outputs in the H. pylori -positive patients ( r  = −0.591 and r  = −0.641, respectively; P  < 0.01), and significantly decreased with concomitant increases in acid secretions after eradication of H. pylori . [¹⁴C]-aminopyrine uptake was inhibited by IL-1β in a dose-dependent manner.
Conclusions : Increased production of IL-1β caused by H. pylori infection is possibly involved in the inhibition of acid secretion in enlarged fold gastritis.     

Effect of food and gender on the pharmacokinetics of tucaresol in healthy volunteers

Aims To investigate the nasal absorption of hydroxocobalamin in 10 healthy elderly adults.
Methods In a cross-over study, blood samples were collected before administration of the drug and after 10, 20, 30, 40, 60, 120, 180 and 240  min. The plasma cobalamin concentration was determined by competitive radioisotope binding technique.
Results The maximal plasma cobalamin concentration ( C _max ) after nasal administration of 750  μg hydroxocobalamin was 1900±900  pmol  l⁻¹ (mean±s.d.). The maximal plasma cobalamin concentration was reached in 35±13  min ( t _max ). The C _max after nasal administration of 1500  μg hydroxocobalamin was 3500±2500  pmol  l⁻¹ with a t _max of 28±16  min. Both the AUC(0,240  min) and AUC(0,00) increased significantly with an increase of the dose from 750  μg to 1500  μg ( P =0.037 and P =0.028, respectively). The nasal spray was well tolerated. No signs of irritation or local sensitivity were noted.
Conclusions The nasal absorption of hydroxocobalamin in healthy elderly adults is rapid, high and well tolerated.     

Chronic heart failure: β-blockers and pharmacogenetics

Purpose  The European Society of Cardiology recommends that β-blockers should be considered for treating all patients with stable, mild, moderate, or severe heart failure (HF) who are receiving standard treatment, unless there is a contraindication. Despite the significant benefit of the drug, there is widespread recognition of patient-to-patient variability in drug response. The genetic determinants of responses to drugs have important implications for the clinical course and management of HF. Pharmacogenetics (PGt) has drawn great attention for its potential to redirect personal care and public health paradigms. The aim of this review was to gather information on PGt of β-blockers in HF treatment. Methods  We searched for articles related to PGt of β-blockers in the PubMed database and attempted to cover all related articles. Results  Several genetic polymorphisms affecting proteins in the β-adrenergic receptor signaling pathway have been proposed as modifiers of HF risk. The most relevant of these to this review is the pharmacogenetic interactions between the genetic variants of catecholamine receptors or their effectors and β-blockade for the treatment of HF. Conclusions  Interindividual variability of responsiveness to β-blockers can be explained by PGt data of adrenaline-related genes. To demonstrate that pharmacogenetic intervention produces successful individualized β-blocker treatment for HF patients, prospective, randomized, and pharmacogenomics (PGx)-based clinical trials are required. Our assessment is that we are already at a turning point in the history of clinical pharmacology.     

The role of fatty acid hydrolase gene variants in inflammatory bowel disease

Background  Recent studies suggest a role for the endocannabinoid system, including fatty acid amide hydrolase (FAAH), in intestinal inflammation.
Aim  To analyse FAAH expression and the FAAH 385 C/A (p.Pro129Thr; rs324420) single nucleotide polymorphism (SNP) in-patients with Crohn's disease (CD) and ulcerative colitis (UC).
Patients and methods  Genomic DNA from 1008 individuals (CD: n  = 435; UC: n  = 167; controls: n  = 406) was analysed for the FAAH 385 C/A SNP. We determined FAAH mRNA expression by quantitative PCR in CD and UC lesions as well as in intestinal epithelial cells (IECs).
Results  There were no significant differences regarding the frequency of this SNP in the three study groups (CD, UC, controls). However, CD patients homozygous for the FAAH p.Pro129Thr polymorphism were more likely to develop a severe disease phenotype associated with fistulas ( P  = 0.03, OR 3.12, 95% CI 1.08–8.98) and extra-intestinal manifestations ( P  = 0.005, OR 4.29, CI 1.49–12.35). In UC, homozygous carriers had an earlier disease onset than wild-type carriers ( P  = 0.01). FAAH mRNA expression correlated with IL-8 mRNA expression in CD lesions ( r  = 0.53). However, pro-inflammatory stimuli did not significantly increase FAAH mRNA expression in IECs.
Conclusion  The FAAH p.Pro129Thr polymorphism may modulate the CD phenotype.     

Stereoselective interaction between piroxicam and acenocoumarol

1 An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers.
2 Eight healthy male volunteers received an oral dose of 4  mg rac -acenocoumarol on days 1 and 8, plus 40  mg piroxicam orally 2  h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24  h interval.
3 The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: C _max+28.0% (s.d.23.8), P <0.05; AUC(0,  24  h)+47.2% (21.5), P <0.005; and t _1/2+38.0% (34.5), P <0.01. A concomitant decrease of CL/ F was observed: −30.8% (10.0), P <0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: C _max: +9.5% (s.d.36.6), AUC(0,  24  h): +15.4% (23.4), t _1/2: +19.9% (42.0), and CL/ F: −9.8% (20.5). V/F remained unchanged for both enantiomers.
4 Piroxicam plasma AUC(0,  24  h) correlated closely with R- and Sacenocoumarol AUCs on day 1 ( r =0.901, P <0.005 and r =0.797, P <0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol ( r =0.903, P <0.001) and S-acenocoumarol ( r =0.711, P <0.05).
5 Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.     

Effects of cardioselective and non-cardioselective beta-blockade on adrenaline-induced metabolic and cardiovascular responses in man

Summary In 12 normal volunteers the interaction between the metabolic and cardiovascular effects of adrenaline and either a cardioselective (atenolol 150 mg p. o. for 1 week) or a non-selectiveβ-blocker with intrinsic sympathomimetic activity (pindolol 15 mg p. o. for 1 week) were studied. Equiactive doses of theβ-blockers were investigated with respect to their metabolic effects. There were profound differences in the metabolic profile of the two substances: the non-cardioselective beta-blocker caused significant inhibition of the lipolytic, glycogenolytic and the growth hormone-releasing effects of adrenaline when compared to the cardioselective agent. The results indicate that, during non-cardioselective beta-blockade, metabolic effects occur which should favourably influence myocardial oxygen consumption by making myocardial performance more economical.     

The pharmacokinetics of ziprasidone in healthy volunteers treated with cimetidine or antacid

Aims  To evaluate the effects of cimetidine and Maalox^® (aluminium hydroxide 1.35 g and magnesium hydroxide 1.2 g) on the pharmacokinetics of ziprasidone.
Methods   Eleven healthy young subjects aged 18–45 years were given single oral doses of ziprasidone 40 mg on three occasions at least 7 days apart. On one occasion ziprasidone was administered alone, on another occasion ziprasidone was co‐administered with oral cimetidine 800 mg and on a third occasion ziprasidone was co‐administered with oral Maalox^®.
Results   The administration of cimetidine increased the ziprasidone AUC(0,∞) by 6% but there were no statistically significant differences in C _max, t _max or λ_z between the ziprasidone+cimetidine group and the ziprasidone group. The administration of Maalox^® did not produce any statistically significant differences in AUC(0,∞), C _max, t _max or λ_z between the ziprasidone+Maalox^® group and the ziprasidone group.
Conclusions   The pharmacokinetics of ziprasidone are not affected by concurrent administration of cimetidine or Maalox^®. This suggests that other nonspecific inhibitors of cytochrome P450 and antacids are unlikely to alter the pharmacokinetics of ziprasidone.     

Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis C

Background  The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated.
Aim  To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin.
Patients and methods  Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment.
Results  At week 4, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.376, P  = 0.002) and AUC _0→12h of ribavirin plasma level ( r  = −0.277, P  = 0.018). At week 12, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.384, P  < 0.0001) and AUC _0→12h of ribavirin plasma level ( r  = −0.257, P  = 0.002). In genotype 1 patients, AUC _0→12h ribavirin and C _min were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12.
Conclusion  C_min of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR.     

Effect of age and gender on the pharmacokinetics of eprosartan

Aims To compare the pharmacokinetics of eprosartan between young (18–45 years) and elderly (65 years) men and between young men and young, premenopausal women (18–45 years).
Methods Twenty-four subjects (eight subjects/group) received a single 200  mg eprosartan oral dose followed by serial blood sampling over 24  h.
Results Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (≈98%) for the three groups. On average, AUC (0,∞) and C _max values were ≈2-fold higher in elderly men than young men [AUC (0,∞) 95% CI: 1.22, 4.34; C _max 95% CI: 0.98, 4.00]. Similarly, unbound AUC (0,∞) and C _max values were, on average, ≈2-fold higher in elderly men than young men [unbound AUC (0,∞) 95% CI: 1.29, 4.44; unbound C _max 95% CI: 1.02, 4.12]. t _max was delayed in the elderly men compared with young men, with a median difference of 2.5  h (95% CI: 1.00, 3.01  h).
Conclusions No gender differences were observed in the pharmacokinetics of eprosartan. There were ≈  two fold higher AUC and C _max values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200  mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.     

Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A

Aims In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N -demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N -demethylation of IMI.
Methods Healthy subjects were given troleandomycin (TAO), a selective inhibitor of CYP3A, 250  mg daily for 2 days before a single oral dose of 100  mg IMI was administered.
Results Pretreatment with TAO significantly increased the AUC of IMI by 59% (1971±938 vs 3134±2000  μg l⁻¹  h, 95% confidence interval for difference between means: 218 to 2108  μg  l⁻¹  h, P <0.05) and decreased its oral clearance by 30% (60.9±27.4 vs 42.5±22.7  l h⁻¹, 95% confidence internal for difference between means: 7.2 to 31.7  l h⁻¹, P <0.05).
Conclusions We conclude that CYP3A may play an important role in the in vivo N -demethylation of IMI.     

Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-β-1a in moderately active ulcerative colitis

Background  Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-β-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms and thus represents a potential treatment.
Aim  To extend pilot data and identify a suitable dose of IFN-β-1a to achieve endoscopically confirmed remission (ECR) in patients with moderately active UC and to evaluate safety.
Methods  In this multicentre, double-blind, placebo-controlled trial, adults with moderately active UC were randomized to IFN-β-1a 44 or 66 μg, or placebo, subcutaneously three times weekly for 8 weeks, with a 4-week follow-up.
Results  Endoscopically-confirmed remission was observed in 23.4% [95% confidence interval (CI): 13.8–35.7] of placebo patients, 29.2% (95% CI: 18.6–41.8) of the IFN-β-1a 44 μg group and 20.0% (95% CI: 11.1–31.8) of the 66 μg group ( P  = 0.45). Improvements with IFN-β-1a 44 μg were greater than with placebo for most secondary efficacy outcomes, although significance was not achieved. Placebo response rates were higher than expected from previous trials. Adverse events were similar to the known safety profile of IFN treatment.
Conclusions  Interferon-β-1a was generally well tolerated at the doses tested, but a significant therapeutic benefit in patients with UC was not observed.     

Diltiazem increases blood concentrations of cyclized cyclosporine metabolites resulting in different cyclosporine metabolite patterns in stable male and female renal allograft recipients

1 Six male and six female stable renal allograft recipients under cyclosporine immunosuppression and without concomitant therapy with drugs known either to induce or inhibit CYP3A enzymes were included in the study and received 180  mg day⁻¹ diltiazem for 1 week in a two-period cross-over fashion. Cyclosporine (352±56  mg day⁻¹) was given in two daily oral doses. The daily doses were not changed during the study. Blood samples were collected for 12  h after receiving cyclosporine alone and after receiving diltiazem in addition for 1 week. Cyclosporine and nine of its metabolites were quantified using h.p.l.c.
2 Co-administration of diltiazem caused a 1.6 fold increase of the AUC(0,12  h) of cyclosporine and a 1.7 fold increase of the AUC(0, 12  h) of its metabolites. Analysis of the metabolite patterns showed an over-proportional increase of the AUC(0, 12  h) of the cyclized metabolites AM1c (2.6 fold) and AM1c9 (2.2 fold). The AUC(0, 12  h) values of cyclosporine and the hydroxylated metabolites increased less than two fold.
3 Differences of the AUC(0, 12  h) values of cyclosporine with and without diltiazem were significantly higher in female than in male patients ( P <0.02). The differences in the AUC(0, 12  h) values of the metabolites, especially AM1c, tended to be higher in female patients as well.
4 It is concluded that coadministration of diltiazem not only increases the blood concentration of cyclosporine but also those of its metabolites, leads to a shift of the metabolite pattern towards cyclized metabolites, and that the pharmacokinetic changes under diltiazem administration are more prominent in female than in male patients.     

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200  mg artemether. Blood samples were collected to 72  h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153  μg  l⁻¹, were reached 1.88±0.21  h after drug intake. The mean elimination half-life was 2.00±0.59  h, and the mean AUC 671±271  μg  l⁻¹ h. The mean C _max of DHA, 273±64  μg  l⁻¹, was observed at 1.92±0.13  h. The mean AUC of DHA was 753±233  μg  h  l⁻¹. ARM and DHA were stable at ≤−20°  C for at least 4 months in plasma samples.
Conclusions The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26°  C) it is recommended to store them at a temperature of ≤−20°  C as early as possible after sample collection.     

Atenolol and metoprolol: Comparison of effects on blood pressure and serum lipoproteins,and side effects

Summary Several -blockers increase VLDL-TG and decrease HDL-cholesterol concentrations. The underlying mechanism ist not yet clear. Some studies have suggested that the effect is less pronounced during treatment with selective -blockers. The effects of 2 such drugs, metoprolol 200 mg/day and atenolol 50 mg/day, have been compared in 50 hypertensive patients (WHO Stage I–II), mean age 47 years. Serum lipoproteins were determined in 20 patients before treatment and after treatment with either drug for 3 months. Both drugs were equally effective in reducing blood pressure. After atenolol the initial VLDL-cholesterol concentration of 1.04 mmol/l had not changed, but it rose to 1.29 mmol/l after metoprolol (p<0.05). The HDL-cholesterol concentration 1.42 mmol/l did not fall during atenolol treatment, but during metoprolol there was a small reduction to 1.31 mmol/l (p<0.05). Hyperlipoproteinaemia is common in hypertensive patients, 40% of the present group had hypertriglyceridaemia and 25% had hypercholesterolaemia. Thus, atenolol 50 mg was found not to affect lipoproteins, whereas metoprolol 200 mg increased the VLDL concentration in 75% of the patients.     

Inhibition of cytochrome P450 3A by clarithromycin uniformly affects the pharmacokinetics and pharmacodynamics of oxycodone in young and elderly volunteers

The aim of this study was to investigate the effect of the cytochrome P450 3A4 inhibitor clarithromycin on the pharmacokinetics and pharmacodynamics of oral oxycodone in young and elderly subjects. Ten young and 10 elderly healthy subjects participated in this placebo-controlled, randomized, 2-phase crossover study. Subjects took clarithromycin 500 mg or placebo twice daily for 5 days. On day 4, subjects ingested an oral dose of 10 mg oxycodone. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 hours, and pharmacological response for 12 hours. Clarithromycin decreased the apparent clearance of oxycodone by 53% in young and 48% in elderly subjects (P < 0.001) and prolonged its elimination half-life. The mean area under the plasma concentration-time curve (AUC0-∞) of oxycodone was increased by 2.0-fold (range, 1.3-fold to 2.7-fold) (P < 0.001) in young and 2.3-fold (range, 1.1-fold to 3.8-fold) (P < 0.001) in elderly subjects. The formation of noroxycodone was decreased by 74% in young and 71% in elderly subjects (P < 0.001). The ratio of AUC0-∞ of oxycodone during the clarithromycin phase compared with the one with placebo did not differ between the age groups. Clarithromycin did not alter the pharmacological response to oxycodone. Clarithromycin increased the exposure to oral oxycodone, but the magnitude of this effect was not age related. Although the pharmacological response to oxycodone was not significantly influenced by clarithromycin, dose reductions may be necessary in the most sensitive patients to avoid adverse effects when oxycodone is used concomitantly with clarithromycin.     

β(1)-Adrenergic receptor gene polymorphisms and the acute response to atenolol in healthy young Japanese subjects

Polymorphisms at codons 49 and 389 of the β(1)-adrenergic receptor gene have been shown to alter the receptor function in vitro, whereas it remains controversial whether they influence the response to β-blocker in vivo. In the present study, we investigated whether these polymorphisms influence the acute changes of heart rate and blood pressure induced by the β(1)-adrenergic receptor-selective blocker atenolol in healthy young Japanese. A double-blind study was conducted with 307 subjects randomly allocated 2:1 to atenolol (50 mg) or placebo groups. Heart rate and blood pressure were significantly reduced after administration of atenolol in comparison to the placebo. In 207 subjects allocated to the atenolol group, the numbers of Ser/Ser, Ser/Gly, and Gly/Gly allele carriers for codon 49 were 159, 46, and 2, respectively; and those of Arg/Arg, Arg/Gly, and Gly/Gly for codon 389 were 129, 66, and 12, respectively. No significant association was identified between the changes in heart rate or blood pressure and either of the two polymorphisms. There was also no difference in the changes in heart rate or blood pressure among the diplotypes. The results of the present study do not support clinical use of genotyping for these polymorphisms to predict responses to β-blockers.     

Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19

Aims Omeprazole has been shown previously to be metabolized by the two cytochrome P450 isoforms CYP2C19 (hydroxylation) and CYP3A4 (sulphoxidation). The objective of this study was to test the inducibility of these enzymes by carbamazepine (CBZ).
Methods Omeprazole was given as a single oral dose before and after 3 weeks of treatment of five patients with CBZ (400–600  mg daily).
Results Mean area under the plasma concentration vs time curve (AUC) between 0 and 8  h after drug intake, decreased by about 40% for omeprazole and its hydroxy metabolite and increased for its sulphone metabolite, but the changes were not statistically significant. The ratio of the AUCs of omeprazole and its sulphone, used as an index of CYP3A4 activity, decreased in all patients ( P =0.052), while there was no change in the omeprazole/hydroxyomeprazole AUC ratio used as an index for CYP2C19 activity. There was a significant decrease in the mean ratio of the AUC of the hydroxy and sulphone metabolites from 2.58 to 0.93 ( P =0.046) with a mean difference of 1.79 (95% CI: 0.07 to 3.50) showing that the induction was more pronounced for CYP3A4 than for CYP2C19.
Conclusions CBZ induces CYP3A4, but not, or to a lesser extent, CYP2C19. The induction of the sulphoxidation of omeprazole by CBZ seems to have no major clinical implication.     

The effects of ketoconazole on ziprasidone pharmacokinetics —a placebo‐controlled crossover study in healthy volunteers

Aims   To assess the effects of multiple oral doses of ketoconazole on the single‐dose pharmacokinetics of oral ziprasidone HCl.
Methods   This was a 14‐day, open‐label, randomized, crossover study in 14 healthy subjects aged 18–31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash‐out period and 6 days of placebo administration. Group 2 received placebo followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared between placebo and ketoconazole administration periods.
Results   Co‐administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,∞) increased by 33%, from 899 ng ml^{− 1} h with placebo to 1199 ng ml^{− 1} h with ketoconazole. Mean C _max increased by 34%, from 89 ng ml^{− 1} to 119 ng ml^{− 1}, respectively. The treatment effect on both of these parameters was statistically significant ( P < 0.02). Most adverse events were of mild intensity. There were no serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically significant alterations in vital signs throughout the study.
Conclusions   The concurrent administration of ketoconazole and ziprasidone led to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This suggests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.