Lack of a pharmacokinetic interaction at steady state between ropinirole and L-dopa in patients with Parkinson's disease

STUDY OBJECTIVE: To assess the interaction between therapeutic dosages of ropinirole and L-dopa plus a decarboxylase inhibitor administered at steady state in patients with Parkinson's disease. DESIGN. Open, 6-week, overlap trial with random allocation. PATIENTS: Thirty patients with Parkinson's disease not previously treated with dopamine agonists, of whom 28 produced evaluable pharmacokinetic data for ropinirole and 23 for L-dopa. INTERVENTION: Group A (14 patients) received L-dopa for weeks 1-5 and ropinirole in increasing increments for weeks 2-6; group B (16) received ropinirole for weeks 1-5 and L-dopa for weeks 5 and 6. MEASUREMENTS AND MAIN RESULTS: Primary end points were AUC0-8 and Cmax for ropinirole, and AUC0-8, AUC0-infinity and Cmax for L-dopa. Secondary end points were Tmax for ropinirole, and Tmax and half-life for L-dopa. Coadministration with L-dopa at steady state did not affect rate or extent of availability of ropinirole: point estimates of the geometric mean ratio for ropinirole plus L-dopa compared with ropinirole alone for both Cmax and AUC0-8 approximated to unity. The small (16%) increase in peak concentrations of L-dopa on administration with ropinirole is unlikely to be of clinical consequence, as peak concentrations of L-dopa are typically highly variable. CONCLUSION: There are no pharmacokinetic grounds for adjusting dosages of either ropinirole or L-dopa when given in combination.     

Lack of a kinetic interaction between fluconazole and mexiletine

Objective. To investigate the effect of fluconazole on the kinetics of mexiletine. Methods. Six healthy male volunteers participated in a crossover study. On the 1st day, the subjects received 200 mg mexiletine alone. On days 2–7 they received 200 mg fluconazole orally, and on day 8 they received 200 mg mexiletine and 200 mg fluconazole concomitantly. In a third phase two subjects received 400 mg fluconazole daily. Results. No differences in concentrations were observed between the three phases. The area under the concentration curves (AUC) after administration of mexiletine alone and in combination with fluconazole 200 mg/day were 6.63 and 7.31 μg ⋅ h ⋅ ml⁻¹, respectively. Conclusion. These findings suggest that fluconazole does not inhibit mexiletine metabolism. Received: 7 July 1995/Accepted in revised form: 19 September 1995     

Lack of a pharmacokinetic interaction between steady-state roflumilast and single-dose midazolam in healthy subjects

AIMS: The aim of this study was to investigate the effects of roflumilast, an investigational PDE4 inhibitor for the treatment of COPD and asthma, on the pharmacokinetics of the CYP3A probe drug midazolam and its major metabolites. METHODS: In an open, randomized (for midazolam treatment sequence) study, 18 healthy male subjects received single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart) alone, repeated doses of roflumilast (500 microg once daily for 14 days) alone, and repeated doses of roflumilast together with single doses of midazolam (2 mg oral and 1 mg i.v., 1 day apart). RESULTS: A comparison of clearance and peak and systemic exposure to midazolam following administration of roflumilast indicated no effect of roflumilast dosed to steady state on the pharmacokinetics of midazolam. Point estimates (90% CI) were 0.97 (0.84, 1.13) for the AUC of i.v. midazolam and 0.98 (0.82, 1.17) for that of oral midazolam with and without roflumilast. CONCLUSIONS: Therapeutic steady state concentrations of roflumilast and its N-oxide do not alter the disposition of the CYP3A substrate midazolam in healthy subjects. This finding suggests that roflumilast is unlikely to alter the clearance of drugs that are metabolized by CYP3A4.     

Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline

AIMS: Theophylline is a model substrate of cytochrome P4501A2. The ability of the proton pump inhibitors (PPI) omeprazole, lansoprazole and pantoprazole to induce cytochrome P4501A2 has not yet been unequivocally resolved. The aim of this comprehensive study was to compare directly the effect of the three PPI on the absorption and disposition of theophylline. METHODS: Twenty healthy, nonsmoking, male and female volunteers (extensive metabolisers of cytochrome P4502C19 and Helicobacter pylori negative) participated in a randomized, double-blind, four-period, placebo-controlled crossover study. In each of the four periods they received either omeprazole (40 mg), lansoprazole (60 mg), pantoprazole (80 mg) or placebo once daily for 10 days. Sustained release theophylline (350 mg twice daily) was coadministered from day 8-10. Pharmacokinetics of theophylline as well as of all three PPI were determined at steady-state (day 10). RESULTS: In all periods, point estimates and 90% confidence intervals of the area under the concentration-time curves (AUC), maximum steady-state concentrations and peak-trough fluctuations of theophylline were not altered by PPI pretreatment and met the required limits for bioequivalence. Point estimates (90% confidence intervals) of the AUC ratios of theophylline plus PPI to theophylline alone were 0.92 (0.87-0.97), 0.90 (0.85-0.95) and 1.00 (0.95-1.06) for omeprazole, lansoprazole and pantoprazole, respectively. CONCLUSIONS: Concomitant intake of omeprazole, lansoprazole or pantoprazole at high therapeutic doses does not affect the absorption and disposition of theophylline.     

Linear pharmacokinetic behavior of ropinirole during multiple dosing in patients with Parkinson's disease

The objectives of this study were to measure the pharmacokinetics of ropinirole at steady state when the drug is used as an adjunct to L-dopa and evaluate the long-term tolerability of ropinirole in this indication. Twenty-four patients who were taking L-dopa for Parkinson's disease and experiencing a lack of symptomatic control were recruited. Patients received open-label adjunctive treatment with ropinirole for up to 2 years. The starting dose was 0.5 mg bid, which could be titrated to a maximum of 6.0 mg tid. Ropinirole demonstrated approximately dose-linear pharmacokinetics at steady state; corresponding values were higher during tid than bid dosing. A reduction in mean L-dopa dose was maintained throughout the trial. The combination of L-dopa and ropinirole was generally well tolerated, with only 1 patient withdrawing from treatment because of adverse events. Thus, ropinirole shows approximately linear steady-state pharmacokinetics and a good safety profile when administered with L-dopa.     

Lack of a pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline

AIM: To study the potential pharmacokinetic interaction between lansoprazole or pantoprazole and theophylline at steady state. METHODS: Theophylline 200 mg extended-release formulation was administered twice daily on days 1-11 to 30 healthy, non-smoking males. On days 5-11, 15 subjects received concomitant lansoprazole 30 mg once daily (o.d.) and 15 subjects received concomitant pantoprazole 40 mg o.d. RESULTS: No significant changes in the steady-state theophylline maximum plasma concentration (Cmax), time to Cmax (Tmax), minimum plasma concentration (Cmin), area under the plasma concentration-time curve over the 12-h dosing interval (AUC0-12), or apparent total oral clearance (CL/F) were observed within the two treatment groups when theophylline was administered alone or in combination with lansoprazole or pantoprazole. In addition, no significant differences in the changes of steady-state theophylline pharmacokinetics from day 4 to day 11 were noted between the two treatment groups. Treatment with theophylline in combination with either lansoprazole or pantoprazole was well tolerated. All adverse events were transient and rated mild to moderate in severity. CONCLUSION: Co-administration of either lansoprazole or pantoprazole in healthy subjects does not significantly affect the steady-state pharmacokinetics of theophylline at the therapeutic doses tested.     

Lack of clinically important interaction between erythromycin and theophylline

Summary In 11 healthy volunteers the kinetics of theophylline and the plasma levels and the urinary excretion of its metabolites were studied before and after treatment with erythromycin for 10 days. Theophylline was administered as an intravenous bolus injection (280 mg) followed by a constant intravenous infusion (23.8±4.1 mg/h) for 6 hours. The total clearance of theophylline at steady-state (63.4±9.9 vs 63.8±14.4 ml/min, before vs after erythromycin treatment) and the elimination half-life after cessation of the infusion (6.7±2.6 vs 7.5±1.8 h, before vs after treatment) did not change during the treatment with erythromycin. No difference in the formation of metabolites before and after treatment with erythromycin was detected; the findings in urine were 40.4±5.0 vs 42.1±5.4% 1,3-dimethyluric acid, 29.6±4.6 vs 30.1±5.9% 1-methyluric acid and 13.4±3.5 vs 12.5±2.2% 3-methylxanthine before and after erythromycin treatment, respectively. It is concluded that a clinically relevant interaction between erythromycin and theophylline does not occur.     

Lack of a pharmacokinetic interaction between atovaquone and proguanil

Objective: To assess the magnitude of the putative effect of atovaquone on the pharmacokinetics of proguanil and to determine whether the pharmacokinetics of atovaquone are affected by concomitant administration of proguanil, with both drugs administered for 3 days to healthy adult volunteers. Methods: This was an open-label, randomized, three-way cross-over study, in which 18 healthy volunteers received 400 mg proguanil, 1000 mg atovaquone and 1000 mg atovaquone + 400 mg proguanil. Each treatment was given once daily for 3 days with a 3-week wash-out period between each occasion. For the assay of proguanil, cycloguanil and atovaquone, blood was sampled before dosing and at regular intervals over 8 days when proguanil was given, and over 17 days when atovaquone was given. Results: The geometric mean of the area under the atovaquone plasma concentration-time curve calculated from 0 to 24 h after the last dose (AUC_0→24h) was 180 μg · ml⁻¹ · h following administration of atovaquone alone and 193 μg · ml⁻¹ · h following atovaquone with proguanil. The geometric mean AUC_0→24h for proguanil was 6296 ng · ml⁻¹ · h after proguanil alone and 5819 ng · ml⁻¹ · h following proguanil with atovaquone. The corresponding values for the metabolite cycloguanil were 1297 ng · ml⁻¹ · h and 1187 ng · ml⁻¹ · h, respectively. The geometric mean elimination half-life (t_1/2) of atovaquone was 57.1 h when given alone and 59.0 h when administered together with proguanil. The corresponding geometric mean values of t_1/2 for proguanil were 13.7 h and 14.5 h. Exploratory statistical analysis showed no important gender effects on the pharmacokinetics of atovaquone, proguanil, or cycloguanil. Conclusion: The pharmacokinetics of atovaquone and proguanil and its metabolite, cycloguanil, were not different when atovaquone and proguanil were given alone or in combination. Received: 14 October 1998 / Accepted in revised form: 8 February 1999     

Lack of a pharmacokinetic interaction between moexipril and hydrochlorothiazide

Objective: To investigate the potential for pharmacokinetic interactions between moexipril, a new converting enzyme inhibitor, and hydrochlorothiazide after single dose administration. Methods: 12 healthy male volunteers were studied by an open, randomised, three-way cross-over design, in which single doses of moexipril, hydrochlorothiazide and the two drugs together were administered. Blood and urine were collected up to 48 hours for measurement of the concentrations of moexipril and its metabolite moexiprilat. In addition, the urine samples were analysed for hydrochlorothiazide. Results: For the area under the plasma concentration-time curve calculated from time 0 to a concentration greater than zero, AUC(0–t), the study showed a mean value of moexipril 437 ng ⋅ ml⁻¹⋅ h⁻¹ following administration of moexipril alone and 416 ng ⋅ ml⁻¹⋅ h⁻¹ following moexipril concomitantly with hydrochloro- thiazide. The corresponding values for the metabolite moexiprilat were 203 and 215 ng ⋅ ml⁻¹⋅ h⁻¹, respectively. The c_max of moexipril and the metabolite (data of the metabolite in parenthesis) were 245.4 (70.8) ng ⋅ ml⁻¹ after administration of moexipril alone and 241.0 (69.2) ng ⋅ ml⁻¹ after coadministration of hydrochlorothiazide. The mean total renal excretion (TUE) of hydrochlorothiazide was 15.2 mg when administered alone and 15.1 mg when given together with moexipril. The corresponding mean TUE-values for moexiprilat were 334 (1200) and 453 (1460) μg. Conclusion: The coadministration of moexipril with hydrochlorothiazide had no demonstrable effect on the measured pharmacokinetic parameters of moexipril, its active metabolite moexiprilat or hydrochlorothiazide. Received: 10 July 1995/Accepted in revised form: 3 March 1996     

Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers

Aims

To examine the potential effect of danshen extract on the pharmacokinetics of theophylline.

Methods

In a sequential cross-over study with two phases, 12 volunteers took 100 mg theophylline on day 1 and day 15. From day 2 to day 15, volunteers received danshen extract tablets three times daily, four tablets each time for 14 days. On day 15, they received four danshen extract tablets with 100 mg theophylline. Plasma concentrations of theophylline were measured on days 1 and 15 periodically for 24 h.

Results

The 90% confidence interval of C_max, t_1/2 and CL/F of theophylline with 14-day danshen extract tablets vs. without comedication were (101.42, 121.36) (84.57, 106.72) and (88.82, 105.72), respectively. The time to peak plasma theophylline concentration was unchanged by danshen (P > 0.05). The pharmacokinetics parameter of theophylline was unaffected by danshen extract.

Conclusions

Danshen extract does not influence the metabolism of theophylline in healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with danshen extract tablets.

What is already known about this subject

• Danshen extract is widely used for the treatment and prevention of coronary heart disease and other diseases of senility in Asia.
• Danshen extract and theophylline may be prescribed together to treat patients with asthma.
• In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2.
• In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of danshen and danshen pharmaceutical product.
• There may be drug interactions between danshen extract and theophylline (CYP1A2 substrate).

What this study adds

• This study concerned drug interactions between danshen extract and theophylline in Chinese volunteers.
• Long-term oral intake of danshen extract does not change the basic pharmacokinetic parameters of theophylline.
• Dose adjustment of theophylline thus may not be necessary in patients receiving concomitant therapy with danshen extract.

     

Absence of interaction between erythromycin and a single dose of clozapine

Objective: To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine. Methods: Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval 0–12 h. Results: There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h · 1⁻¹ in the control phase and 1180 (659) nmol h · 1⁻¹ in the erythromycin phase), terminal half-lives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol · 1⁻¹ and 77 (40) nmol · 1⁻¹, respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances of clozapine (34 (15) l · h⁻¹ and 46 (37) l · h⁻¹, respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l · h⁻¹ and 7.8 (9.4) l · h⁻¹, respectively) or to desmethyl-clozapine (1.5 (1.3) l · h⁻¹ and 1.8 (1.7) l · h⁻¹, respectively) or in renal clearances of clozapine (0.8 (0.5) l · h⁻¹ and 1.0 (0.7) l · h⁻¹, respectively) between the two phases. Conclusion: These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose. Received: 26 August 1998 / Accepted in revised form: 8 January 1999     

Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine–alprazolam interaction in patients with psychosomatic disease

Purpose  Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP). Methods  Blood samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also genotyped for CYP2D6. Results  The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged. Conclusions  The extent of interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers.     

Gender difference in the pharmacokinetic interaction between oral warfarin and oxolamine in rats: inhibition of CYP2B1 by oxolamine in male rats

The possible reason for the significantly greater AUC of oral warfarin with oral oxolamine in male Sprague-Dawley rats was evaluated. After oral administration of warfarin at a dose of 2 mg/kg to male rats with oxolamine at doses of 10 and 50 mg/kg, the AUC values of warfarin were significantly greater than the controls (254 and 330 versus 180 microg h/ml). However, the AUC values of warfarin were not affected by oxolamine in female rats. This could be due to inhibition of CYP2B1, 2C11 and 3A2 by oxolamine in male rats, since warfarin was metabolized via CYP1A1, 2B1, 2C6, 2C11 and 3A2 in rats and CYP2B1 is male dominant, and CYP2C11 and 3A2 are male specific. Therefore, phenytoin, torasemide and clarithromycin (mainly metabolized via CYP2B1/2, 2C11 and 3A2 in rats, respectively) were administered intravenously to male rats with or without oral oxolamine. After oral oxolamine at doses of 10 and 50 mg/kg, the AUC of phenytoin was significantly greater (1280 and 1640 versus 938 microg min/ml), however, the AUC values of torasemide and clarithromycin were independent of oxolamine. The above data suggest that the significantly greater AUC of oral warfarin with oral oxolamine could be due to inhibition of CYP2B1/2 by oxolamine in male rats.     

Negligible pharmacokinetic interaction between oral DA-8159, a new erectogenic, and amlodipine in rats

A pharmacokinetic interaction between oral DA-8159 and amlodipine was evaluated in male Sprague-Dawley rats. In rats pretreated with troleandomycin (a main inhibitor of CYP3A1/2 in rats), the AUC(0-6 h) of amlodipine was significantly greater than the controls (34.5+/-6.01 compared with 28.0+/-4.70 microg min/ml), indicating that amlodipine is metabolized via CYP3A1/2 in rats. It was reported that the metabolism of DA-8159 and the formation of DA-8164 (a metabolite of DA-8159) were mainly mediated via CYP3A1/2 in rats, and amlodipine significantly inhibited the CYP3A2 in rats. Therefore, a pharmacokinetic interaction between the two drugs could be expected. However, after oral administration of DA-8159 at a dose of 30 mg/kg with or without oral amlodipine at a dose of 5 mg/kg to rats, the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between the two groups of rats. Similar results were also obtained from amlodipine between with and without DA-8159. The above data indicated that the pharmacokinetic interaction between oral DA-8159 and amlodipine was almost negligible in rats.     

质子泵抑制剂与氯吡格雷的药物相互作用解析

近年来,临床研究发现氯吡格雷合用质子泵抑制剂（proton pump inhibitors,PPI）可能会增加急性冠脉综合征（acute coronary syndrome,ACS）或经皮冠状动脉介入（percutaneous coronary intervention,PCI）术后患者心血管不良事件发生的风险,因此,联合用药存在争议。本文从氯吡格雷与CYP2C19多态性、PPI与氯吡格雷在药理及临床作用上的相互影响、相关临床研究来深入解析药物相互作用。药代动力学研究的Meta分析结果显示,PPI可能削弱了氯吡格雷抗血小板的效应。10个临床观察性研究都体现了这个观点,但文献质量偏低,而其余3篇低质量的观察性研究、5篇中等质量的观察性研究和1篇高质量的RCT均未发现氯吡格雷合用PPI会显著增加患者心血管不良事件的发生风险。     

反相HPLC法同时测定人尿中茶碱及其两种代谢产物

目的:建立一种同时测定人尿中茶碱及其1,3-二甲基尿酸(1,3-DMU)和3-甲基噻嗪(3-MX)代谢产物的HPLC方法.方法:尿样用异丙醇/二氯甲烷(2/8)混合液提取,有机相在空气吹干,用流动相复溶后进行HPLC分析.色谱柱为Diamonsil ODS C_(18)5 μm,150 mm×4.6 mm I.D),流动相由0.1%甲酸液和乙腈(95:5)组成,流速1.0 mL/min,测定波长280 nm.测定12名受试者单剂量和多剂量口服茶碱后24 h内尿中茶碱及其代谢物累计排泄量.结果:尿中茶碱及其代谢物1,3 DMU和3-MX的线性范围分别为0.312～40.0、0.156～20.0、0.078～10.μg/mL,最低可定量浓度分别为0.312、0.156、0.078μg/mL.批间和批内的变异小于15%,回收率大于70%.结论:该方法的特异性、灵敏度能够满足临床上对人尿中茶碱及其代谢产物同时测定的要求.     

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     

Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man

Objective: Pantoprazole is a selective proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzymes in man. Due to the clinical importance of an interaction with anticoagulants, this study was carried out to investigate the possible influence of pantoprazole on the pharmacodynamics and pharmacokinetics of phenprocoumon. Methods: Sixteen healthy male subjects were given individually adjusted doses of phenprocoumon to reduce prothrombin time ratio (Quick method) to about 30–40% of normal within the first 5–9 days and to maintain this level. The individual maintenance doses remained unaltered from day 9 on and were administered until day 15. Additionally, on study days 11–15, pantoprazole 40 mg was given per once daily. As a pharmacodynamic parameter, the prothrombin time ratio was determined on days 9 and 10 (reference value) and on days 14 and 15 (test value), and the ratio test/reference was evaluated according to equivalence criteria. Results: The equivalence ratio (test/reference) for prothrombin time ratio was 1.02 (90% confidence interval 0.95–1.09), thus fulfilling predetermined bioequivalence criteria (0.70–1.43). The pharmacokinetic characteristics AUC_0–24h and C_max of S(−)-and R(+)-phenprocoumon were also investigated using equivalence criteria. Equivalence ratios and confidence limits of AUC_0–24h and of C_max of S(−)-phenprocoumon (0.93, 0.87–1.00 for AUC_0–24h; 0.95, 0.88–1.03 for C_max) and of R(+)-phenprocoumon (0.89, 0.82–0.96; 0.9, 0.83–0.98) were within the accepted range of 0.8–1.25. Conclusion: Pantoprazole does not interact with the anticoagulant phenprocoumon on a pharmacodynamic or pharmacokinetic level. Concomitant treatment was well tolerated. Received: 26 January 1996/Accepted in revised form:22 May 1996     

A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism

Objective: Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder. Method: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. Results: The dose of olanzapine given after a 2-week pre-treatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for C_max and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased. Conclusion: Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population. Received: 22 July 1997 / Accepted in revised form: 1 June 1998