Lack of correlation between fluvoxamine clearance and CYP1A2 activity as measured by systemic caffeine clearance

Objective: Evidence exists to suggest that fluvoxamine is metabolized by CYP1A2. The present study was undertaken in order to further elucidate the role of CYP1A2 in fluvoxamine disposition. Methods: Twelve healthy non-smoking male volunteers participated in this cross-over study. Six subjects received first fluvoxamine 50 mg as a single oral dose and, some weeks later, caffeine 200 mg as a single oral dose. The other six subjects received the drugs in reverse order. Serum concentrations of fluvoxamine, caffeine and paraxanthine were measured and standard pharmacokinetic parameters were calculated. Results: There were no significant correlations between caffeine clearance and fluvoxamine oral clearance (r _s= −0.30; P = 0.43) or between the paraxanthine/caffeine ratio in serum 6 h after caffeine intake and fluvoxamine oral clearance (r _s= −0.18; P = 0.58). Conclusion: CYP1A2 does not appear to be of major importance in the metabolism of fluvoxamine. Received: 10 July 1998 / Accepted in revised form: 4 October 1998     

Pharmacokinetics of sertindole and dehydrosertindole in volunteers with normal or impaired renal function

Objective: To study the effect of renal impairment on the pharmacokinetics of sertindole. Methods: A single 4 mg oral dose of sertindole was given to normal subjects ( n = 6) and subjects with various degrees of impaired renal function ( n = 18) classified into mild, moderate, and severe/hemodialysis based on their creatinine clearance). The relationships between the pharmacokinetic parameters and the degree of renal impairment were investigated using regression analysis with creatinine clearance as an explanatory variable along with body weight. Subjects were also genotyped for CYP2D6-A or 2D6-B mutations. Results: The mean CL/f and t_1/2 values of sertindole ranged from 14 to 31 l · h⁻¹ and from 73 to 93 h, respectively, and were not significantly related to creatinine clearances. There was no indication of any influence of creatinine clearance on the fraction of sertindole (0.994–0.995) binding to plasma proteins. The total fraction of the sertindole dose removed by dialysis was less than 0.1%. Subjects with B/B genotype ( n = 2) for CYP2D6 were associated with a distinctly lower clearance of sertindole (6.3 vs 25.3 l · h⁻¹) than subjects with wt/wt genotype for CYP2D6. Conclusions: Since the pharmacokinetics of sertindole are unchanged by renal impairment, dosage adjustment does not appear to be necessary for subjects with various degrees of renal insufficiency or subjects with renal failure requiring hemodialysis. Received: 19 August 1996 / Accepted in revised form: 9 January 1997     

Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data

Objective: The purposes of this study were to identify the P450 enzyme (CYP) responsible for zonisamide metabolism in humans by using expressed human CYPs and to predict drug interaction of zonisamide in vivo from in vitro data. Methods: Ten expressed human CYPs and human liver microsomes were used in the experiments for the identification of enzymes responsible for zonisamide metabolism and for the prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data, respectively. Two-sulfamoylacetyl phenol, a reductive metabolite of zonisamide, was measured by the HPLC method. Results: From the experiments using ten expressed human CYPs, CYP2C19, CYP3A4 and CYP3A5 were shown to be capable of catalyzing zonisamide reduction. However, an intrinsic clearance, V_max/k_M, of CYP3A4 was much higher than those of CYP2C19 and CYP3A5. From the point of view of enzyme amount in human liver CYPs isoform and their intrinsic clearance, it was suggested that CYP3A4 is mainly responsible for zonisamide metabolism in human CYPs. Zonisamide metabolism in human liver microsomes was markedly inhibited by cyclosporin A, dihydroergotamine, ketoconazole, itraconazole, miconazole and triazolam. We estimated the possibility and degree of change of zonisamide clearance in vivo in clinical dose range from in vitro inhibition constant of other drugs against zonisamide metabolism (Ki) and unbound inhibitor concentration in blood (Iu) in clinical usage. Clearance of zonisamide was maximally estimated to decrease by 31%, 23% and 17% of the clearance without inhibitors i.e. ketoconazole, cyclospolin A and miconazole, respectively. Fluconazole and carbamazepine are estimated to decrease by 5–6% of the clearance of zonisamide. On the other hand, there may be lack of interaction of zonisamide metabolism by dihydroergotamine, itraconazole and triazolam in clinical dose range. Conclusion: We demonstrated that: (1) zonisamide is metabolized by recombinant CYP3A4, CYP2C19 and CYP3A5, (2) the metabolism is inhibited to a variable extent by known CYP3A4/5 substrates and/or inhibitors in human liver microsomes, and (3) in vitro-in vivo predictive calculations suggest that several compounds demonstrating CYP3A4-affinity might cause in vivo drug-drug interactions with zonisamide. Received: 12 June 1997 / Accepted in revised form: 17 November 1997     

Fluvoxamine is a potent inhibitor of tacrine metabolism in vivo

Objective: In vitro studies have shown that tacrine is metabolized by cytochrome P4501A2 (CYP1A2). One of the monohydroxy-metabolites has been incriminated with tacrine-induced hepatotoxicity. The aim of this study was to establish whether the potent CYP1A2 inhibitor fluvoxamine in clinically relevant doses could inhibit tacrine metabolism. Methods: Eighteen healthy young men were enrolled in an open, randomized crossover study. In the first study period a single oral dose of tacrine 40 mg was given. In the second period the volunteers were randomized to maintenance doses of fluvoxamine 50 or 100 mg per day, and a single oral dose of tacrine 20 mg was given. Results: Fluvoxamine was found to be a very potent inhibitor of tacrine metabolism. A fractional decrement in tacrine clearance of approximately 85% was found with both fluvoxamine doses, which was in good agreement with a prediction based on in vitro data. The medians of the steady-state concentration of fluvoxamine were 43 nM (range 25–49) and 70 nM (range 44–124) in the 50 mg per day and 100 mg per day groups, respectively. The steady-state concentration of fluvoxamine correlated with the fractional decrement in tacrine clearance (Spearman R_s = 0.53, P < 0.05). Modest, but statistically significant, reductions in the formation of the metabolites 1- and 2-hydroxytacrine were found during concomitant fluvoxamine treatment. Conclusion: Fluvoxamine at clinically relevant doses is a potent inhibitor of tacrine metabolism. This interaction is very likely to have clinical relevance. Whether concomitant fluvoxamine treatment reduces tacrine-induced hepatotoxicity needs further study. Received: 16 September 1998 / Accepted in revised form: 27 January 1999     

Grapefruit juice has no effect on quinine pharmacokinetics

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

Dose-dependent alternations in the pharmacokinetics of olanzapine during coadministration of fluvoxamine in patients with schizophrenia

Olanzapine, an atypical antipsychotic agent, is a substrate of the cytochrome P4501A2 (CYP1A2) enzyme. Administration of a potent CYP1A2 inhibitor (eg, fluvoxamine) may alter the pharmacokinetics of olanzapine. This study investigated the pharmacokinetic interactions between olanzapine and fluvoxamine in patients with schizophrenia. Ten male smokers were administrated a single dose of olanzapine 10 mg at baseline, followed by 2 weeks of fluvoxamine 50 mg/day and another 2 weeks of fluvoxamine 100 mg/day. Olanzapine 10 mg was given at day 10 during each fluvoxamine treatment. After pretreatment with fluvoxamine, the area under the curve, maximal plasma concentration, and half-time of olanzapine were significantly increased by 30% to 55%, 12% to 64%, and 25% to 32%, respectively. Volume of distribution and apparent clearance were significantly reduced by 4% to 26% and 26% t O 38%, respectively, after administration of fluvoxamine. Increases in area under the plasma concentration-time curve from time 0 to infinity appear to be dose dependent. Presumably, altered olanzapine pharmacokinetics are attributed to the inhibition of CYP1A2. Patients treated with the combination of olanzapine and fluvoxamine should be monitored carefully.     

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

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

Lack of Effect of Olanzapine on the Pharmacokinetics of a Single Aminophylline Dose in Healthy Men

Study Objective . To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. Design . Two-way, randomized, crossover study. Setting . Clinical research laboratory. Subjects . Nineteen healthy males (16 smokers, 3 nonsmokers). Interventions . Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. Measurements and Main Results . Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4′-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline. Conclusion . As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.     

Non-response to maprotiline caused by ultra-rapid metabolism that is different from CYP2D6?

Case: We are reporting about a patient with major depression who failed to respond to pharmacotherapy due to ultra-rapid metabolism of maprotiline. Under daily oral doses of 175 mg maprotiline, the patient's metabolic ratio (MR) for maprotiline in plasma was 9.2 (expected MR_p: 2.4) and the clearance of maprotiline (CL_M) was 4190 ml · min⁻¹ (expected CL_M = 1220 in extensive metabolisers of CYP2D6). Results: The patient's MR_urine for sparteine was 0.5, which is within the range for extensive metabolisers of CYP2D6. Genotyping did not show a duplication of the CYP2D6L allele. The patient's caffeine half-life was 10 h, thus, precluding ultra-rapid metabolism for CYP1A2. The therapeutic regimen was changed to coadministration of 200 mg maprotiline and 20 mg fluoxetine once per day in order to inhibit metabolism via CYP2D6. Subsequently, MR_p of maprotiline (4.9) and CL_M were reduced (1900 ml · min⁻¹; expected CL_M in poor metabolisers: of CYP2D6 364). This regimen improved the clinical outcome of the underlying disease. Conclusion: We conclude that for the non-response seen with maprotiline, P450 isozymes other than CYP2D6 or CYP1A2 are responsible. As CYP2C19 is involved in the metabolism of a number of tricyclic antidepressants it may be a candidate for ultra-rapid metabolism in this patient. Received: 11 October 1996 / Accepted in revised form: 6 February 1997     

Influence of fluoxetine on olanzapine pharmacokinetics

Conventional antidepressant treatment fails for up to 30% of patients with major depression. When there are concomitant psychotic symptoms, response rates are even worse. Thus, subsequent treatment often includes combinations of antidepressants or augmentation with antipsychotic agents. Atypical antipsychotic agents such as olanzapine cause fewer extrapyramidal adverse effects than conventional antipsychotics; for that reason, they are an advantageous augmentation strategy for treatment-resistant and psychotic depression. The purpose of this study was to assess the potential for pharmacokinetic interaction between olanzapine and fluoxetine, a popular antidepressant that is a selective serotonin reuptake inhibitor. The pharmacokinetics of 3 identical single therapeutic doses of olanzapine (5 mg) were determined in 15 healthy nonsmoking volunteers. The first dose of olanzapine was taken alone, the second given after a single oral dose of fluoxetine (60 mg), and the third given after 8 days of treatment with fluoxetine 60 mg, qd. Olanzapine mean C _max was slightly higher (by about 18%) and mean CL/F was slightly lower (by about 15%) when olanzapine was coadministered with fluoxetine in single or multiple doses. Olanzapine mean t _1/2 and median t _max did not change. Although the pharmacokinetic effects of fluoxetine on olanzapine were statistically significant, the effects were small and are unlikely to modify olanzapines safety profile. The mechanism of influence is consistent with an inhibition of CYP2D6, which is known to control a minor pathway of olanzapine metabolism.     

Effect of 4-tert-octylphenol on cytochrome P450 enzymes in rat liver

The effects were studied of 4-tert-octylphenol (OP) on hepatic cytochrome P450 enzymes in rats. Rats were treated intraperitoneally with OP twice, at doses of 5, 10, and 20 mg/kg. Among the cytochrome P450-dependent monooxygenase activities, testosterone 2α-hydroxylase activity, which is associated with CYP2C11, was significantly decreased by OP at all doses. The level relative to control activity was 67–22%. CYP3A2-dependent monooxygenase, testosterone 6β-hydroxylase activity was also decreased by 51% by OP at 20 mg/kg. Furthermore, immunoblotting showed that OP (10 or 20 mg/kg) significantly decreased CYP2C11/6 and CYP3A2/1 protein levels. However, the reduction ratio of CYP2C11/6 and CYP3A2/1 protein levels by OP treatment was lower than that of testosterone 2α-hydroxylase and testosterone 6β-hydroxylase activities. The Cl _int (V _max/K _m) value for testosterone 2α-hydroxylase was significantly decreased by OP at all doses, whereas the Cl _int value for testosterone 6β-hydroxylase was only decreased by OP at 20 mg/kg. In addition, 7-ethoxycoumarin O-deethylase activity was significantly decreased by 32% by the highest dose of OP. By contrast, CYP1A1-, CYP1A2-, CYP2A1-, CYP2B1/2-, CYP2D1-, CYP2E1- and CYP4A1/2/3- dependent monooxygenase activities were not affected by OP at any dose. These results suggest that OP changes the male-specific cytochrome P450 isoforms in rat liver, and that these changes closely relate to the toxicity of OP. Received: 29 September 1999 / Accepted: 18 October 1999     

Effect of fluvoxamine on the pharmacokinetics of quinidine

Objective: To investigate the possible involvement of cytochromes CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine. Methods: This was an open study of six healthy young male volunteers. The pharmacokinetics of a 200-mg single oral dose of quinidine were studied before and during daily treatment with 100 mg fluvoxamine. Biomarkers of other isozyme activities in the form of caffeine, sparteine, mephenytoin, tolbutamide and cortisol metabolism were applied. Results: The results showed a statistically significant median reduction of 29–44% in the quinidine total apparent oral clearance, partial clearances by 3-hydroxylation and N-oxidation and residual clearance during fluvoxamine treatment. Renal clearance was unaffected by fluvoxamine. Conclusions: The effect of fluvoxamine on the formation clearances of 3-hydroxyquinidine and quinidine-N-oxide most likely reflects inhibition of cytochrome P ₄₅₀3A4 by fluvoxamine at clinically relevant doses. The results of this study do not rule out a possible involvement of CYP1A2 and CYP2C19 in the in vivo oxidative metabolism of quinidine. Received: 16 December 1998 / Accepted in revised form: 5 March 1999     

Lack of differences in diclofenac (a substrate for CYP2C9) pharmacokinetics in healthy volunteers with respect to the single CYP2C9 * 3 allele

Objectives: Evidence exists to suggest that diclofenac is metabolised by CYP2C9. The present study was undertaken in order to evaluate the effect of the single CYP2C9*3 variant on drug metabolism using diclofenac as a probe drug. Methods: A single dose of diclofenac was administered orally to 12 healthy subjects in whom the genotype of CYP2C9 had been determined previously. The disposition kinetics of diclofenac were compared between homozygotes for the wild type (CYP2C9*1/*1, n=6) and heterozygotes for the Leu359 variant (CYP2C9*1/*3, n=6). Results: For diclofenac, the following kinetic parameters were observed in the CYP2C9*1/*1 and CYP2C9*1/*3 subjects, respectively (mean ± SD): apparent oral clearance (ml/kg/h) 355.8 ± 56.9 and 484.4 ± 155.3; area under plasma concentration–time curve (μg h/ml) 2.7 ± 0.7 and 1.9 ± 0.6. The formation clearance of 4′-hydroxydiclofenac (ml/kg/h) was 63.6 ± 19.1 in the CYP2C9*1/*1 subjects compared with 75.9 ± 27.6 in the CYP2C9*1/*3 subjects. There were no significant differences in any of the kinetic parameters for either diclofenac disposition or formation clearance of 4′-hydroxydiclofenac between the two genotype groups. Conclusion: Since the disposition kinetics of diclofenac does not change in subjects with the single CYP2C9*3 mutant allele, it is suggested that the effects of CYP2C9 polymorphisms on the drug metabolism tend to be substrate specific. Received: 4 October 1999 / Accepted in revised form: 12 January 2000     

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

Objective: We studied a possible pharmacokinetic interaction between clozapine and itraconazole, a potent CYP3A4 inhibitor. Methods: A double-blind randomized study design was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 200 mg itraconazole or placebo for 7 days. For the next 7 days, itraconazole was changed to placebo and vice versa. Serum concentrations of clozapine and its main metabolite desmethylclozapine were measured on days 0, 3, 7, 10 and 14. Results: Concomitant administration of itraconazole had no significant effect on serum concentrations of clozapine or desmethylclozapine. Conclusion: CYP3A4 seems to be of minor importance in clozapine metabolism in humans. Itraconazole, and probably also other inhibitors of CYP3A4, can be used concomitantly with clozapine. Received: 8 August 1997 / Accepted in revised form: 14 December 1997     

A model for the determination of carbamazepine clearance in children on mono- and polytherapy

Objective: To derive a model describing carbamazepine (CBZ) clearance in children, in terms of individual patient characteristics. Methods: One hundred and eighteen steady-state serum carbamazepine concentration measurements were gathered during normal routine care of 72 compliant out-patients (2.3–16.3 years old). Levels were obtained from patients receiving monotherapy (55%), concomitant valproate (26%), or concomitant inducers (phenytoin, phenobarbitone; 19%). A one-compartment model was used to fit the data with the computer programme Nonlinear Mixed Effects Model (NONMEM). Results: Weight, age and concomitant medication were all important determinants of clearance. The final model for clearance (l · h⁻¹) was: CL = [0.7(WT)^0.4] · M, where WT is patient weight (kg) and M is a scaling factor for concomitant medication, with a value of 1 for patients on CBZ monotherapy or concomitant valproate and 1.4 for those receiving concomitant inducers. For the purposes of this analysis, bioavailability (f) was assumed to be complete, i.e., f is thus included in the term CL. Conclusions: CBZ clearance decreased with increasing age. As age and weight were correlated, either variable was a satisfactory predictor. The influence of both the inducers and valproate on CBZ clearance was as expected. This model, which describes clearance in terms of patient-specific details, can be used when predicting the maintenance dose required to achieve a target mean steady-state CBZ concentration in children. Received: 10 May 1997 / Accepted: 16 February 1998     

Effect of fluconazole on plasma fluvastatin and pravastatin concentrations

Objective: To study the effects of fluconazole on the pharmacokinetics of fluvastatin and pravastatin, two inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Methods: Two separate randomised, double-blind, two-phase, crossover studies with identical study design were carried out. In each study, 12 healthy volunteers were given a 4-day pretreatment with oral fluconazole (400 mg on day 1 and 200 mg on days 2–4) or placebo, according to a randomisation schedule. On day 4, a single oral dose of 40 mg fluvastatin (study I) or 40 mg pravastatin (study II) was administered orally. Plasma concentrations of fluvastatin, pravastatin and fluconazole were measured over 24 h. Results: In study I, fluconazole increased the mean area under the plasma fluvastatin concentration–time curve (AUC_0–∞) by 84% (P < 0.01), the mean elimination half-life (t _1/2) of fluvastatin by 80% (P < 0.01) and its mean peak plasma concentration (C_max) by 44% (P < 0.05). In study II, fluconazole had no significant effect on the pharmacokinetics of pravastatin. Conclusions: Fluconazole has a significant interaction with fluvastatin. The mechanism of the increased plasma concentrations and prolonged elimination of fluvastatin is probably inhibition of the CYP2C9-mediated metabolism of fluvastatin by fluconazole. Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are prescribed to patients using fluvastatin. However, pravastatin is not susceptible to interactions with fluconazole or other potent CYP2C9 inhibitors. Received: 25 October 1999 / Accepted in revised form: 9 March 2000     

CYP2C9 genotypes and the quality of anticoagulation control with warfarin therapy among Brazilian patients

Objective To evaluate the impact of the two most common CYP2C9 variant alleles (*2 and *3) on the maintenance dose of warfarin and on the quality of anticoagulation control in Brazilians. Methods Patients (n = 103) initiated warfarin therapy with 5 mg/day (or 2.5 mg/day when over 80 years old). The international normalized ratio (INR) was targeted between 2 and 3, monitored every week until four consecutive adequate measures had been obtained, and then monthly. Serious hemorrhagic events were defined by the need for inpatient hospitalization. CYP2C9 genotyping was obtained by PCR-RFLP. Results The frequencies of CYP2C9*2 and CYP2C9*3 were 0.097 and 0.073, respectively, with genotypic distribution fitting Hardy-Weinberg equilibrium. CYP2C9 genotype was the only clinical feature associated with the risk of severe bleeding (one-sided P = 0.019, Fisher exact method), with an odds ratio of 4.8 (95% confidence interval of 1.4–16.6) for any variant genotype as compared to CYP2C9*1*1. Patients with either CYP2C9*2 or CYP2C9*3 were equally difficult to maintain in the INR target range, showing significantly (one-sided P = 0.038, Mann-Whitney U-test) reduced ratio of adequate INR measures (0.54 ± 0.2), when compared to CYP2C9*1*1 patients (0.63 ± 0.2). Patients with CYP2C9*3, but not CYP2C9*2, required significantly (one-sided P = 0.001, Mann-Whitney U-test) lower warfarin maintenance doses (3.1 ± 1.8 mg) than CYP2C9*1*1 patients (5.3 ± 2.1 mg). Conclusion Patients with either CYP2C9*2 or CYP2C9*3 show higher risk of over-anticoagulation compared to CYP2C9*1*1 subjects and could benefit from a reduction in the initial warfarin standard dose (e.g., to 2.5 mg/day).     

Correlation of cytochrome P450 (CYP) 1A2 activity using caffeine phenotyping and olanzapine disposition in healthy volunteers.

Olanzapine has previously been shown to have predominant metabolism by cytochrome (CYP) P450 1A2. Caffeine has been shown to provide an accurate phenotypic probe for measuring CYP1A2 activity. The purpose of this study is to determine if a significant correlation exists between olanzapine disposition and caffeine metabolic ratios. Subjects were phenotyped for CYP1A2 activity with caffeine probe methodology. After 200-mg caffeine administration, blood (4 h), saliva (6 and 10 h), and urine (8 h total) were collected for high-performance liquid chromatography (HPLC) analysis of caffeine and its metabolites.CYP1A2 activity was measured as plasma (PMR(4 h)), saliva (SMR(6 h) and SMR(10 h)), and three urinary metabolic (UMR1(8 h), UMR2(8 h), and UMR3(8 h)) ratios. Each of the 14 healthy nonsmokers (13 male) received a single 10 mg olanzapine dose after which blood was collected for HPLC determination of olanzapine concentrations at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 h postdose. Olanzapine pharmacokinetic parameters in this study were similar to those previously published. All caffeine metabolic ratios (PMR(4 h), SMR(6 h), SMR(10 h), UMR1(8 h), and UMR2(8 h)) significantly correlated with each other (p <0.001) except for UMR3(8 h), which did not correlate. A significant correlation (p <0.05) was also found between olanzapine clearance and PMR(4 h) (r=0.701), SMR(6 h) (r=0.644), SMR(10 h) (r=0.701), UMR1(8 h) (r=0.745), and UMR2(8 h) (r=0.710). A negative correlation was observed between olanzapine clearance and UMR3(8 h) (r=-0.029, p=NS). A significant correlation was found between olanzapine clearance and various caffeine metabolic ratios. Interpatient variability in CYP1A2 activity may explain the wide interpatient variability in olanzapine disposition. Compounds that modulate CYP1A2 activity may be expected to alter olanzapine pharmacokinetics accordingly.     

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

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

Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine

Objective To compare the long-term efficacy and safety of aripiprazole with olanzapine in patients with either acute relapsing or chronic, stable schizophrenia.Materials and methods A 52-week, open-label extension to a 26-week, multicenter, randomized, double-blind, placebo-controlled trial in patients with chronic schizophrenia. Patients who completed the initial treatment or who met the protocol definition of relapse after ≥2 weeks of double-blind treatment were randomized to aripiprazole (15–30 mg/day, n = 104) or olanzapine (10–20 mg/day, n = 110) for 52 weeks.Results Sixty-nine percent of patients completed the study. Efficacy improvements were similar between groups at endpoint, mean reductions in Positive and Negative Syndrome Scale (PANSS) Total scores from baseline for patients completing the study (observed cases) were similar in chronic stable patients (aripiprazole, −7.94; olanzapine, −7.36) and in patients with acute relapse (aripiprazole, −31.19; olanzapine, −29.55). Olanzapine-treated patients reported more extrapyramidal symptoms (EPS)-related adverse events (18%) than aripiprazole-treated patients (10%). No significant differences in EPS were seen between treatments at endpoint. Olanzapine was associated with significantly greater weight gain than aripiprazole at all time points (week 52 [LOCF]: +2.54 vs +0.04 kg; p < 0.001). Changes in fasting glucose and lipid levels at endpoint favored aripiprazole over olanzapine, with significant differences observed for total cholesterol, low- and high-density lipoprotein. While differences observed for changes in fasting glucose and triglycerides favored aripiprazole, they were not statistically significant.Conclusion Aripiprazole showed similar efficacy to olanzapine for long-term treatment of acutely psychotic and chronic, stable schizophrenia patients, with a lower liability for weight gain or increased lipid levels.