甘草对阿普唑仑在大鼠体内药动学特征的影响

目的研究甘草对阿普唑仑在大鼠体内药动学特征的影响。方法将14只SD大鼠随机分为对照组与实验组,分别予生理盐水和甘草提取物(0.5 g·kg^-1,qd×7d),灌胃给予阿普唑仑20 mg·kg^-1后按时间点连续采样,采用HPLC法测定血药浓度。采用DAS 2.0软件计算并比较主要药动学参数。结果对照组和实验组中阿普唑仑的主要药动学参数:ρ_max分别为（1 015.24±706.67）、（1170.81±682.69）μg·L（¹）,t_max分别为（0.52±0.18）、（0.52±0.18）h,t_1/2分别为（3.57±0.91）、（3.21±0.61）h,AUC_0→12h分别为（1 067.03±482.19）、（1 283.76±504.07）μg.h·L^-1,AUC_0→∞分别为（1 081.17±478.07）、（1 299.04±501.17）μg·h·L^-1MRT分别为（1.77±0.75）、（1.78±0.64）h。各参数在两组间比较,差异均无统计学意义（P>0.05）。结论甘草连续给药7 d后不影响阿普唑仑在大鼠体内的药动学特征。     

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     

Lack of interaction of ranitidine with amitriptyline

Summary The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.     

不同剂量阿普唑仑在大鼠体内的药动学研究

3组大鼠分别按50、20和2 mg·kg~(-1)阿普唑仑悬液,ig,体内动力学特征均符合一室开放模型.各组的吸收和消除参数无明显差异,平均值(n=18)K_a=3.3454 h~(-1).K.=0.3873 h~(-1),T_((1/2)k_(?))=0.29 h,T((1/2)K_(?))=2.61h,T_(max)=1.04 h。血药浓度与给药剂量呈正相关,3组的C_(max)(n=6)分别为4.5764、2.1793和0.2256μmol·L~(-1),r=0.6096(P<0.005);AUC分别为28.31、8.42和2.13 h·μmol·L~(-1),r=0.6854(p<0.001)、各剂量组的血药浓度和药动学参数均存在较大个体差异。     

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     

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 interaction between meloxicam and warfarin in healthy volunteers

Objective: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. Results: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUC_SS values for the more potent S-enantiomer were 5.07 mg · h · l⁻¹ (27.5%) for warfarin alone and 5.64 mg · h · l⁻¹ (28.1%) during the interaction phase. Respective AUC_SS values for R-warfarin were 7.31 mg · h · l⁻¹ (43.8%) and 7.58 mg · h · l⁻¹ (39.1%). Conclusion: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory. Received: 13 May 1996 / Accepted in revised form: 29 August 1996     

Pharmacokinetic interaction between fluoxetine and metoclopramide in healthy volunteers

The pharmacokinetic interaction of fluoxetine with metoclopramide in healthy volunteers was evaluated. A dose of 20 mg metoclopramide in combination with 60 mg fluoxetine was administered to 24 healthy male volunteers in a two treatment study design, separated by 8 days in which the fluoxetine alone was administered as a single p.o. dose daily. Plasma concentrations of metoclopramide were determined during a 24 h period following drug administration. Metoclopramide plasma concentrations were determined by a validated HPLC method. Pharmacokinetic parameters of metoclopramide were calculated using non-compartmental analysis. In the two periods of treatment, the mean peak plasma concentrations (Cmax) were 44.02 ng/ml (metoclopramide alone) and 62.72 ng/ml (metoclopramide after pre-treatment with fluoxetine). The times taken to reach Cmax and tmax, were 1.15 h and 1.06 h, respectively. The total areas under the curve (AUC(0-infinity)) were 312.61 ng.h/ml and 590.62 ng.h/ml, respectively. The half-life values (t1/2) were 5.52 h and 8.47 h. Statistically significant differences were observed for both AUC(0-infinity) and t1/2 of metoclopramide when administered alone or after 8 days treatment with fluoxetine. The experimental data demonstrate the pharmacokinetic interaction between fluoxetine and metoclopramide and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.     

A pharmacokinetic interaction between roxithromycin and midazolam

The interaction between roxithromycin and midazolam was investigated in a double-blind, randomised crossover study of two phases. Ten healthy volunteers were given roxithromycin (300 mg) or placebo once daily for 6 days. On the sixth day they ingested 15 mg midazolam. Plasma samples were collected and psychomotor performance measured for 17 h.Roxithromycin administration significantly increased the area under the plasma midazolam concentration-time curve from 8.3 to 12.2 g·ml^–1·min and the elimination half-lives from 1.7 to 2.2 h. In psychomotor performance only minor differences were seen between the treatments in one of the measured psychomotor parameters.Thus, in contrast to the strong interaction between erythromycin and midazolam, the interaction between roxithromycin and midazolam appears less likely to be clinically significant.Presented in part at the 18th International Congress of Chemotherapy, Stockholm, Sweden, June 27–July 2, 1993     

Lack of interaction between metoclopramide and morphine in vitro and in mice

1.?This study examined interactions via common metabolism or via common pharmacodynamic pathways between frequently co-prescribed metoclopramide (a prokinetic) and morphine (an opioid analgesic).

2.?In human liver microsomes, morphine 3-glucuronide and morphine 6-glucuronide formation had V_max estimates of 6.2 ± 0.07 and 0.75 ± 0.01 (nmole min^?1 mg^?1 protein) and K_m estimates of 1080 ± 37 and 665 ± 55 (µM), respectively. The in vitro K_i for morphine 3-glucuronide formation in the presence of metoclopramide in human liver microsomes or recombinant uridine diphosphoglucuronosyltransferase 2B7 predicted a lack of in vivo interaction.

3.?Morphine (2 mg kg^?1 subcutaneously) delayed gastrointestinal meal transit in mice, metoclopramide (10 mg kg^?1 subcutaneously) had no effect on meal transit, and metoclopramide did not alter this effect of morphine.

4.?Morphine (2 or 5 mg kg^?1 subcutaneously) was antinociceptive in mice (hot plate test) and metoclopramide (10 mg kg^?1 subcutaneously) did not alter the antinociceptive effects of morphine.

5.?Together, the data suggest a lack of interaction between morphine and metoclopramide.     

Pharmacokinetic interaction between fluvastatin and diltiazem in rats

The present study aimed to investigate the effect of fluvastatin on the pharmacokinetics of diltiazem in rats. Pharmacokinetic parameters of diltiazem were determined in rats following an oral administration of diltiazem (15 mg/kg) in the presence and absence of fluvastatin (0.6 and 2.0 mg/kg). Compared with the control given diltiazem alone, the C(max) and AUC of diltiazem increased by 30-70% in rats with the concurrent use of fluvastatin, while there was no significant change in T(max) and the plasma half-life (T(1/2)) of diltiazem. Consequently, absolute and relative bioavailability values of diltiazem in the presence of fluvastatin were significantly higher (p<0.05) than those from the control group, implying that fluvastatin could reduce the presystemic extraction of diltiazem. In conclusion, the concurrent use of fluvastatin significantly enhanced the oral exposure of diltiazem in rats.     

Absence of interaction between tenoxicam and warfarin

Summary The influence of tenoxicam on plasma warfarin concentrations and on its anticoagulant effect has been studied in healthy volunteers. Tenoxicam did not alter the plasma warfarin concentration versus time profile. Treatment with it for 14 days had no effect on the average dose of warfarin required to maintain the prothrombin time within a specified range. The coumarin dose index, an indicator of warfarin sensitivity, remained unchanged during tenoxicam administration. The results demonstrate the lack of a clinically relevant effect of tenoxicam on warfarin-induced anticoagulation.     

The influence of disulfiram on the half life and metabolic clearance rate of diphenylhydantoin and tolbutamide in man

Summary Diphenylhydantoin (DPH) and tolbutamide serum levels were studied in ten volunteers before and after 4 days of disulfiram treatment. The mean DPH half life incresed significantly from 11.0±1.2 h to 19.0±3.3 h, and the mean DPH metabolic clearance rate decreased significantly from 51.2±17.2 ml/min to 33.9±12.0 ml/min during medication. No significant changes in the half life or metabolic clearance rate of tolbutamide was observed.     

The use of alprazolam by people who inject drugs in Melbourne, Australia

Introduction and Aims. In Australia, people who inject drugs (PWID) commonly report the use of benzodiazepines (BZDs). This paper explores the emerging use of alprazolam among PWID in Melbourne, Australia. Design and Methods. This study reports on 3 years of data collected through the Victorian Illicit Drug Reporting System (2008–2010). Structured interviews were conducted with 451 PWID and analysed using odds ratios and χ²‐tests for trends over time. Results. While the proportion of PWID reporting recent BZD use remained stable over time, the proportion reporting alprazolam to be their most commonly used BZD fluctuated, peaking in 2009. Alprazolam users were significantly more likely to report using illicit BZDs and to report recent BZD injection compared with users of other BZDs. Alprazolam use was associated with the sale of drugs for cash, but not with other criminal activities. Discussion and Conclusion. The fluctuations in alprazolam use over time may be reflective of medical practitioners ceasing to prescribe alprazolam in response to reports of associated harms; however, this may in turn be driving the illicit alprazolam market. While the data do not indicate a clear association between alprazolam use and harms, considering the potential severity of associated harms and the association between alprazolam use and anterograde amnesia, patterns of alprazolam use among PWID should be closely monitored. Potential changes to prescribing practice should consider unintended consequences, such as replacement with other BZD types, or illicitly obtained BZDs.[Horyniak D, Reddel S, Quinn B, Dietze P. The use of alprazolam by people who inject drugs in Melbourne, Australia. Drug Alcohol Rev 2012;31:585–590]     

Pharmacokinetic interaction study between benazepril and amlodipine in healthy subjects

Pharmacokinetic interaction between benazepril (ACE inhibitor) and amlodipine (calcium channel blocker) was studied in 12 healthy subjects. Single doses of benazepril hydrochloride (10-mg tablet) and amlodipine besylate (tablet equivalent to 5 mg amlodipine) were administered alone or in combination according to a three-way, Latin-Square, randomized crossover design. Serial blood samples were collected following each administration for the determination of benazepril and its active metabolite benazeprilat and amlodipine. The mean values of AUC (0–4 h), C_max andT _max for benazepril given as combination versus given alone were 161 vs 140 ng·h·ml⁻¹, 168 vs 149 ng·ml⁻¹, and 0.5 vs 0.6 h. The mean values of AUC (0–24 h), C_max andT _max for benazeprilat after benazepril given as combination versus given alone were 1470 vs 1410 ng·h·ml⁻¹, 292 vs 257 ng·ml⁻¹, and 1.7 vs 1.5 h. The mean values of AUC (0–144 h), C_max andT _max for amlodipine given as combination versus given alone were 118 vs 114 ng·h·ml⁻¹, 2.5 vs 2.3 ng·ml⁻¹, and 8.3 vs 9.0 h. The differences in these pharmacokinetic parameters between the combination and monotherapy treatments were not statistically significant based on ANOVA. The results of this study indicate that no pharmacokinetic interaction existed between the two drugs.     

Evaluation of pharmacokinetic interaction between cyclosporin A and probucol in rats

Purpose. The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. Methods. The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun® capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral® capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. Results. The area under the blood concentration-time curve (AUC) after the administration of Sandimmun® (corn oil) and Neoral® (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral® (saline), it was unchanged. The terminal elimination rate constant was not affected by probucol in any type of cyclosporin A solution. The solubility of cyclosporin A or tacrolimus in water dropped to 49% or 16% of the respective control in the presence of probucol. Conclusion. The interaction between cyclosporin A and probucol is caused by the decreased absorption of cyclosporin A partly based on the lowered solubility in the presence of probucol.     

Lack of interaction between HEPP,a new antiepileptic agent,and carbamazepine in rabbits

The effect of the combination of a new anticonvulsant drug HEPP and carbamazepine (CBZ) on the pharmacokinetics of HEPP and CBZ was investigated using rabbits as an animal model. The study was performed in 18 male New Zealand white rabbits which were randomly divided into three groups, according to a balanced incomplete block design of three treatments and two periods. Plasma concentrations for HEPP and CBZ were assayed using HPLC methods. The results showed that the pharmacokinetic parameters C(max), AUC and t(1/2) were not statistically different when HEPP was administered alone and with CBZ, (AUC(0-alpha) 82.86+/-19.40 vs 83.24+/-12.56 microg h ml(-1); t( 1 2 beta) 3.40+/-0.29 vs 3.36+/-0.45 h; C(max) 18.93+/-2.99 vs 19.79+/-2.68 microg ml(-1) and T(max) 1.27+/-0.16 vs 1.22+/-0.11 h for HEPP alone and HEPP plus CBZ respectively. Evaluation of the pharmacokinetic parameters of CBZ showed, AUC(0-inf) 61.5+/-21.7 vs 67.4+/-23.8 microg h ml(-1); t(12) 4.60+/-1.54 vs 4.41+/-1.35 h; C(max) 8.45+/-3.83 vs 8.70+/-2.59 microg ml(-1) when the drug was administered alone and CBZ plus HEPP, respectively. Our data indicate that there is no effect on the pharmacokinetics of either HEPP or CBZ, when they are administered simultaneously.     

Pharmacokinetic interaction between efavirenz and ketoconazole in rats

1. It is well known that efavirenz and ketoconazole act as an inducer and inhibitor of CYP3A4, respectively. As a result of these actions, co-administration of these drugs may result in changes in the pharmacokinetic parameters of one or both of them.

2. Duodenum-cannulated rats have been used to compare the effect of intraduodenal (KC_i.d.) and intravenous administration of ketoconazole (KC_i.v.) on the pharmacokinetics of efavirenz after intraduodenal administration, as well as the potential effect of efavirenz as a CYP450 inducer on ketoconazole pharmacokinetic profile.

3. While KC_i.v. did not show any significant effect on efavirenz pharmacokinetic profile, KC_i.d. increased significantly (p < 0.05) the peak concentration (C_max) and the area under the plasma concentration–time curve (AUC) of efavirenz by 25.5% and 44.5%, respectively. In addition, the time necessary to reach peak concentration (T_max) increased markedly by 71%. However, the mean total clearance (CL/F) of efavirenz was significantly decreased by 45%. Efavirenz did not produce any alteration in ketoconazole pharmacokinetics.

4. These findings suggest that when the treatment starts with enteral administration of ketoconazole, the inhibitor effect on CYP450 prevails over the inducer effect of efavirenz.

     

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     

Minor and clinically non-significant interaction between toloxatone and amitriptyline

Summary The possibility of a pharmacokinetic interaction between amitriptyline and toloxatone (a new MAOI-A) has been studied in 17 depressed in-patients.Amitriptyline and its demethylated and hydroxylated metabolites in blood and urine were measured at steady state after the administration of amitriptyline with and without toloxatone in steady state. The metabolic status of patients was determined using the dextromethorphan phenotyping test.There was only a minor pharmacokinetic interaction between amitriptyline (AMT) and toloxatone, with a small increase in the AMT/NT (nortriptyline) plasma ratio: 0.68 before and 0.78 after toloxatone. The urinary excretion and plasma levels of AMT and its metabolites were not affected by the co-therapy.Three of the patients were poor metabolisers, but this did not predict the magnitude of the drug interaction.The interaction does not justify plasma level monitoring of amitriptyline as the change in pharmacokinetics was so small.