Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

Objective  Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects. Methods  Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days. Results  For R-warfarin, mean ± SD C_max was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC_0-t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for C_max and 1.247 (1.170–1.327) for AUC_0-t . For S-warfarin, mean ± SD C_max was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC_0-t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for C_max and 0.914 (0.875–0.954) for AUC_0-t . No differences were found for the pharmacodynamic parameter (INR). Conclusion  Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance.     

Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin

Objective To examine the effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Aprepitant is a neurokinin-1 (NK₁)-receptor antagonist developed as an antiemetic for chemotherapy-induced nausea and vomiting.Methods This was a double-blind, placebo-controlled, randomized, two-period, parallel-group study. During period 1, warfarin was individually titrated to a stable prothrombin time (expressed as international normalized ratio, INR) from 1.3 to 1.8. Subsequently, the daily warfarin dose remained fixed for 10–12 days. During period 2, the warfarin dose was continued for 8 days, and on days 1–3 administered concomitantly with aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) or placebo. At baseline (day –1 of period 2) and on day 3, warfarin pharmacokinetics was investigated. INR was monitored daily. During period 2, warfarin trough concentrations were determined daily.Results The study was completed by 22 healthy volunteers (20 men, 2 women). On day 3, steady-state pharmacokinetics of warfarin enantiomers after aprepitant did not change, as assessed by warfarin AUC_0-24h and C_max. However, compared with placebo, trough S(–) warfarin concentrations decreased on days 5–8 (maximum decrease 34% on day 8, P<0.01). The INR decreased after aprepitant with a mean maximum decrease on day 8 of 11% versus placebo (P=0.011).Conclusion These data are consistent with a significant induction of CYP2C9 metabolism of S(–) warfarin by aprepitant. Subsequently, in patients on chronic warfarin therapy, the clotting status should be monitored closely during the 2-week period, particularly at 7–10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.     

Effect of rutin on warfarin anticoagulation and pharmacokinetics of warfarin enantiomers in rats

Objectives The effects of the flavonoid rutin on the anticoagulant activity of oral warfarin and the protein binding and pharmacokinetics of its enantiomers were investigated in rats. Methods A single dose of racemic warfarin, 1.5 mg/kg, was administered orally to rats either alone or on day 5 of an 8‐day oral regimen of rutin, 1 g/kg daily. Results Rutin reduced the anticoagulant effect of racemic warfarin, evident as a 31% reduction in the area under the prothrombin complex activty–time curve (P < 0.05). Key findings Rutin had no apparent effect on pre‐treatment baseline blood coagulation. It enhanced the in‐vitro serum protein binding of S‐ and R‐warfarin (reflected by 40% and 26% reductions in unbound fraction, respectively), and thus restricted distribution by 33 and 21%, respectively. Treatment with rutin significantly decreased the elimination half‐life of S‐warfarin by 37% as a result of the 69% increase in unbound clearance of the S‐enantiomer. This effect was attributed to a significant 77% increase in the unbound formation clearance of the overall oxidative and reductive metabolites, and an increase in the unbound renal clearance of the more potent S‐enantiomer of warfarin. Conclusions Concurrent rutin administration is likely to reduce the anticoagulant effect of racemic warfarin, reflecting a significant decrease in the elimination half‐life of the more potent S‐enantiomer.     

Effect of 5-fluorouracil on the anticoagulant activity and the pharmacokinetics of warfarin enantiomers in rats.

The interaction between the antineoplastic agent 5-fluorouracil (5-FU) and the oral anticoagulant warfarin enantiomers was investigated in rats. An increase in hypoprothrombinaemic response, assessed by means of percent changes of prothrombin complex activity and clotting factor VII activity, to warfarin, was observed following oral administration of 1.5 mg/kg racemic warfarin to rats during a 8-day intraperitoneal dose regimen of 5-FU (13.3 mg/kg daily). 5-FU had no apparent effect on the baseline blood coagulation, the in vitro rat serum protein binding as well as the absorption and distribution of the S- and R-enantiomers of warfarin in rats. Yet treatment with 5-FU produced a significant decrease in the total serum clearance value of S-warfarin in rats. The decreased total clearance was attributed mainly to a significant decrease in the formation rate of the overall oxidative metabolites of the more potent S-enantiomer of warfarin.     

华法林和阿司匹林联用在大鼠体内的药代动力学研究(英文)

目的:探讨华法林和阿司匹林联用在大鼠体内非稳态和稳态条件下的药代动力学相互作用的规律,为临床合理药物联用提供依据。方法:将大鼠随机分为3组,即华法林组(0.2mg/kg),阿司匹林组(10mg/kg),华法林(0.2mg/kg)+阿司匹林组(10mg/kg)联用组,每组6只,给大鼠灌胃,连续6d,在第1天和第6天多个时间点取样,分析和比较非稳态和稳态下血药浓度时间曲线和药代动力学参数。结果:华法林药动学用二室模型描述,阿司匹林药动学用一室模型描述。在非稳态和稳态下,阿司匹林单用和联用的血药浓度-时间曲线相似,药代动力学参数之间均无统计学差异;在非稳态下,华法林单用和联用的血药浓度-时间曲线也类似,但在稳态下,联用的血药浓度时间曲线明显高于单用时的曲线,药代动力学计算结果也表明联用时的AUC和Cmax较单用时较大,且有统计意义。结论:当华法林和阿司匹林联用达到稳态时,阿司匹林对华法林的药动学参数有影响,增大了华法林的暴露(AUC和Cmax)。提示两药联用时,很可能增大患者的出血风险,临床上药物联用时应该注意。     

Irbesartan does not affect the steady-state pharmacodynamics and pharmacokinetics of warfarin

Objectives: To determine whether the initiation or titration of irbesartan alters the pharmacodynamics and/or pharmacokinetics of warfarin in a clinically significant manner, thereby requiring additional monitoring of the anticoagulant effect of warfarin. Methods: Daily doses of warfarin were administered to 16 healthy males for 21 days (10 mg on day 1 and 2.5–10 mg on days 2–21). Irbesartan (300 mg/day) or placebo was concomitantly administered on days 15–21. The pharmacodynamic parameters prothrombin time (PT) and prothrombin time ratio (PTR) were evaluated throughout the study. Plasma and urine samples were collected before and up to 24 h after administration on days 14, 15 and 21 for the determination of the maximum concentration (C_max), time to reach C_max (t_max), the area under the concentration–time curve (AUC) of S-warfarin and the cumulative urinary excretion of warfarin and its metabolites. Pre-dose plasma samples were also collected to determine the C_min of S-warfarin (days 12, 13, 14 and 21) and irbesartan (days 19, 20 and 21). Results: Analysis of PTR data revealed no significant difference between the group mean PTR values at day 22 and those at day 15 (P=0.699). S-warfarin concentrations in plasma and urine, as well as the urinary concentrations of the metabolites of warfarin, were not affected by concomitant single- or multiple-dose administration of irbesartan. Plasma C_min concentrations of S-warfarin and irbesartan were also not affected. Conclusions: No clinically important effect of irbesartan on the pharmacodynamics and pharmacokinetics of warfarin are likely to occur during concomitant administration; therefore, neither a dosage adjustment of irbesartan or warfarin nor any additional monitoring of the anticoagulant effect of warfarin is necessary. Received: 10 December 1998 / Accepted in revised form: 29 June 1999     

Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects*

ABSTRACT

Objective: Vildagliptin is a potent and selective dipeptidyl peptidase?IV (DPP?4) inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha and beta-cell responsiveness to glucose. This study assessed the effect of multiple doses of vildagliptin 100?mg once daily on warfarin pharmacokinetics and pharmacodynamics following a single 25?mg oral dose of warfarin sodium.

Research design and methods: Open-label, randomized, two-period, two-treatment crossover study in 16 healthy subjects.

Results: The geometric mean ratios (co-administration vs. administration alone) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) of vildagliptin, R- and S?warfarin were 1.04 (0.98, 1.11), 1.00 (0.95, 1.04) and 0.97 (0.93, 1.01), respectively. The 90% CI of the ratios for vildagliptin, R- and S?warfarin maximum plasma concentration (C_max) were also within the equivalence range 0.80–1.25. Geometric mean ratios (co-administration vs. warfarin alone) of the maximum value and AUC for prothrombin time (PT_max, 1.00 [90% CI 0.97, 1.04]; AUC_PT, 0.99 [0.97, 1.01]) and international normalized ratios (INR_max, 1.01 [0.98, 1.05]; AUC_INR, 0.99 [0.97, 1.01]) were near unity with the 90% CI within the range 0.80–1.25. Vildagliptin was well tolerated alone or co-administered with warfarin; only one adverse event (upper respiratory tract infection in a subject receiving warfarin alone) was reported, which was judged not to be related to study medication.

Conclusions: Co-administration of warfarin with vilda­gliptin did not alter the pharmacokinetics and pharmaco­dynamics of R- or S?warfarin. The pharmacokinetics of vildagliptin were not affected by warfarin. No dosage adjustment of either warfarin or vildagliptin is necessary when these drugs are co-medicated.     

A study of the effects of zimeldine on the pharmacokinetics and pharmacodynamics of temazepam in healthy volunteers

In this double-blind two-period crossover study, ten healthy volunteers received either 200 mg zimeldine each morning for 5 days, or placebo on the same schedule. On day 5 they received 20 mg temazepam 2 h after zimeldine or placebo. A battery of psychometric tests and subjective measurements was carried out on days 4 and 5. Blood samples were collected on day 5 for pharmacokinetic analysis of temazepam.All the measures of psychomotor performance showed the effects of temazepam, as did two of the subjective measures, the alert/drowsy and steady/dizzy visual analogue scales. No effect of zimeldine alone on performance or subjective state was seen. Zimeldine showed no discernible interaction with the effects of temazepam as assessed by subjective reports, by psychomotor tests, or by pharmacokinetic analysis.     

Physiological pharmacokinetics and pharmacodynamics of (+/-)-verapamil in female rats

Tissue distribution and pharmacodynamics of verapamil were evaluated during steady state intravenous (i.v.) infusion and after single dose intraperitoneal (i.p.) drug administration to female Sprague-Dawley rats. In one group of rats, verapamil was infused to a steady state concentration at which time animals were killed. Verapamil-induced decreases in mean arterial pressure (MAP) were monitored during infusion and correlated with concomitantly obtained plasma verapamil concentrations. Tissue (lung, liver, renal medulla, renal cortex, cardiac muscle, skeletal muscle, perirenal fat, brain stem, cerebral cortex, and cerebellum) and plasma samples were obtained immediately after animals were killed and verapamil and norverapamil concentrations determined. Another group of rats, after receiving i.p. verapamil, were killed at 1, 3, 5, 19, and 24 h. Elimination from each tissue evaluated was described by a first order process. Elimination half-life of verapamil was similar among plasma and tissues evaluated (1.5 to 2.2 h). The per cent verapamil not bound to plasma proteins was concentration-independent and similar between rats receiving i.p. (mean +/- S.D.) (2.28 +/- 0.72 per cent) and i.v. (2.08 +/- 0.03 per cent) verapamil. MAP and verapamil concentration in plasma (r = 0.75; p less than 0.01) and cardiac muscle (r = -0.82; p less than 0.01) were inversely correlated in a highly significant fashion during both i.v. and i.p. drug administrations. The tissue-to-plasma distribution ratio for verapamil and norverapamil was similar among animals receiving i.p. verapamil at all points of sampling, suggesting distribution equilibrium had been achieved. After steady state i.v. infusion, both verapamil and norverapamil tissue: plasma concentration ratios were greater than after i.p. administration. Higher tissue: plasma verapamil concentration ratios after i.v. administration than after i.p. administration suggest either only a pseudoequilibrium is attained after i.p. administration or that determinants of tissue distribution of racemic verapamil differ with different routes of drug administration. In these studies, MAP provided a reasonable pharmacodynamic marker for verapamil tissue and plasma concentrations.     

Effect of cimetidine and phenobarbital on metabolite kinetics of omeprazole in rats

Omeprazole (OMP) is a proton pump inhibitor used as an oral treatment for acid-related gastrointestinal disorders. In the liver, it is primarily metabolized by cytochrome P-450 (CYP450) isoenzymes such as CYP2C19 and CYP3A4. 5-Hyroxyomeprazole (5-OHOMP) and omeprazole sulfone (OMP-SFN) are the two major metabolites of OMP in human. Cimetidine (CMT) inhibits the breakdown of drugs metabolized by CYP450 and reduces the clearance of coadministered drug resulted from both the CMT binding to CYP450 and the decreased hepatic blood flow due to CMT. Phenobarbital (PB) induces drug metabolism in laboratory animals and human. PB induction mainly involves mammalian CYP forms in gene families 2B and 3A. PB has been widely used as a prototype inducer for biochemical investigations of drug metabolism and the enzymes catalyzing this metabolism, as well as for genetic, pharmacological, and toxicological investigations. In order to investigate the influence of CMT and PB on the metabolite kinetics of OMP, we intravenously administered OMP (30 mg/kg) to rats intraperitoneally pretreated with normal saline (5 mL/kg), CMT (100 mg/kg) or PB (75 mg/kg) once a day for four days, and compared the pharmacokinetic parameters of OMP. The systemic clearance (CLt) of OMP was significantly (p<0.05) decreased in CMT-pretreated rats and significantly (p<0.05) increased in PB-pretreated rats. These results indicate that CMT inhibits the OMP metabolism due to both decreased hepatic blood flow and inhibited enzyme activity of CYP2C19 and 3A4 and that PB increases the OMP metabolism due to stimulation of the liver blood flow and/or bile flow, due not to induction of the enzyme activity of CYP3A4.     

Effect of omeprazole on the pharmacokinetics of itraconazole

Objective: To investigate the effect of omeprazole on the pharmacokinetics of itraconazole. Methods: Eleven healthy volunteers received a single dose of oral itraconazole (200 mg) on days 1 and 15 and oral omeprazole (40 mg) once daily from day 2 to day 15. Itraconazole pharmacokinetics were studied on days 1 and 15. Results: Concentrations of itraconazole were higher when it was taken alone than when it was taken with omeprazole. With concomitant omeprazole treatment, the mean AUC_0–24 and C_max of itraconazole were significantly reduced by 64% and 66%, respectively. Conclusion: Omeprazole affects itraconazole kinetics, leading to a reduction in bioavailability and C_max. These two drugs should not be used together. Received: 12 November 1997 / Accepted in revised form: 13 January 1998     

Effect of omeprazole and cimetidine on plasma diazepam levels

Summary The effects of steady state dosing with omeprazole and cimetidine on plasma diazepam levels have been studied in 12 healthy males. Single doses of diazepam (0.1 mg · kg⁻¹ i.v.) were administered after one week of treatment with omeprazole 20 mg once daily, cimetidine 400 mg b. d. or placebo, and the treatment was continued for a further 5 days. Blood was collected for 120 h after the dose of diazepam for the measurement of diazepam and its major metabolite desmethyl diazepam. The mean clearance of diazepam was decreased by 27% and 38% and its half-life was increased by 36% and 39% after omeprazole and cimetidine, respectively. Neither drug had any apparent effect on the volume of distribution of diazepam. Desmethyldiazepam appeared more slowly after both omeprazole and cimetidine. It is concluded that the decrease in diazepam clearance was associated with inhibition of hepatic metabolism both by omeprazole and cimetidine. However, since diazepam has a wide therapeutic range, it is unlikely that concomitant treatment with therapeutically recommended doses of either omeprazole or cimetidine will result in a clinically significant interaction with diazepam.     

Effects of ezetimibe on the pharmacodynamics and pharmacokinetics of lovastatin

SUMMARY

Background: Ezetimibe is a cholesterol absorption inhibitor which decreases low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia. This study investigated the potential for pharmacodynamic and/or pharmacokinetic interactions between ezetimibe and lovastatin.

Methods: In a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study, 48 healthy men with hypercholesterolemia (screening LDL-C ≥ 130?mg/dL) who were stabilized and maintained on a National Cholesterol Education Program (NCEP) Step I diet were randomized to one of the following six oral treatments once daily for 14?days: lovastatin 20?mg; lovastatin 20?mg plus ezetimibe 5, 10, or 20?mg; lovastatin 40?mg plus ezetimibe 10?mg; or placebo.

Results: Reported adverse events were generally mild, nonspecific, and similar among treatments. There were no significant changes in safety laboratory test results, including those for enzymes indicative of muscle or liver injury. Co-administration of ezetimibe and lovastatin did not increase the plasma concentrations of lovastatin or β-hydroxylovastatin. In this parallel comparison study there was an apparent decrease in lovastatin exposure, however, the reduction in lovastatin or β-hydroxylovastatin concentrations was not related to the ezetimibe dose and is not considered to be clinically important. Ezetimibe 5, 10, or 20?mg combined with lovastatin 20?mg caused a significantly (?p < 0.01) greater reduction in LDL-C than lovastatin 20?mg alone, with no apparent effect on HDL-C or triglycerides. LDL-C was reduced by 51.0% with ezetimibe 10?mg plus lovastatin 20?mg, 56.0% with ezetimibe 10?mg plus lovastatin 40?mg, 33.2% with lovastatin alone, and 17.3% with placebo.

Conclusions: The co-administration of ezetimibe and lovastatin was well tolerated and resulted in a significantly greater percentage reduction in serum LDL-C concentrations than with lovastatin alone, with an average incremental reduction of 16–18%. Ezetimibe 10?mg appears to be the optimal dose when co-administered with lovastatin 20?mg once daily. Further incremental reductions in LDL-C from the co-administration of ezetimibe and lovastatin are expected only when the dose of lovastatin is increased. The co-administration of ezetimibe and lovastatin has the potential to produce clinically significant reductions in LDL-C compared to either drug alone, with favorable safety and tolerability.     

氟尿嘧啶类抗肿瘤药物与华法林相互作用研究现状

以氟尿嘧啶类药物如5-氟尿嘧啶、卡培他滨和替吉奥等为基础的化疗方案广泛应用于各种实体瘤治疗。肿瘤患者是血栓形成的高危人群,对已发生血栓或合并血栓形成高危因素者推荐抗凝治疗。华法林是目前广泛应用的口服抗凝药。5-氟尿嘧啶、卡培他滨和替吉奥与华法林联用存在相互作用,可能导致国际标准化比值升高和出血症状,华法林停用、减量或换用低分子肝素后多数患者可恢复,少数可能需要输血治疗。氟尿嘧啶类药物与华法林相互作用的机制尚不明确,可能与5-氟尿嘧啶或其代谢产物抑制华法林代谢酶---肝细胞色素P4501C9酶活性有关。     

The effect of fluvastatin on the pharmacokinetics and pharmacodynamics of ezetimibe

ABSTRACT

Objective: The objective of this study was to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and fluvastatin in healthy hypercholesterolemic subjects at clinically-relevant doses and to evaluate the potential for a pharmacokinetic drug interaction between ezetimibe and fluvastatin.

Methods: In a single-center, evaluator-blind, placebo-controlled, multiple-dose, parallel-group study 32 healthy subjects with hypercholesterolemia were randomized to 4 treatments administered once daily for 14 days: ezetimibe 10?mg plus ezetimibe placebo, fluvastatin 20?mg plus ezetimibe placebo, fluvastatin 20?mg plus ezetimibe 10?mg, and ezetimibe placebo. Blood samples were collected to measure serum lipids and to determine steady-state pharmacokinetics.

Results: Ezetimibe 10?mg significantly (?p ≤ 0.01) decreased total-cholesterol and low-density lipoprotein cholesterol (LDL‐C) concentrations compared to placebo at Day 14. Fluvastatin 20?mg also caused a significant (?p = 0.01) reduction in total-cholesterol and a decrease in LDL‐C at Day 14 compared to placebo, however, the decrease in LDL‐C did not reach statistical significance (?p = 0.08). The coadministration of ezetimibe 10?mg and fluvastatin 20?mg caused significantly (?p ≤ 0.01) greater mean percent reductions in LDL‐C and total-cholesterol than fluvastatin 20?mg alone or placebo at Day 14. Fluvastatin had no clinically significant effect on the pharmacokinetics of ezetimibe. On average, ezetimibe appeared to decrease the rate and extent of fluvastatin bioavailability.

Conclusion: Coadministration of ezetimibe and fluvastatin was safe and well tolerated and caused significant incremental reductions in LDL‐C and total cholesterol compared to fluvastatin administered alone. The pharmacokinetics of ezetimibe were not affected by coadministration with fluvastatin. The apparent decrease in fluvastatin exposure on administration with ezetimibe was likely to be due to the parallel study design and two pharmacokinetic outliers and is considered of no clinical significance.     

The effect of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans

Objective: The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers. Methods: The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8–14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor-VII clotting activity. Results: Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S-warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (±SD) of R-6-hydroxywarfarin (31.1 ± 7.4 ml/h baseline; 18.5 ± 4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9 ± 1.3 ml/h baseline; 4.3 ± 1.1 ml/h at end of cimetidine treatment; P < 0.01). Conclusion: Cimetidine stereoselectively affects the steady-state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients. Received: 11 December 1998 / Accepted in revised form: 17 March 1999     

Effect of serum protein binding on pharmacokinetics and anticoagulant activity of phenprocoumon in rats

The relationship among serum protein binding, kinetics of elimination, distribution, and anticoagulant activity of phenprocoumon was investigated in 25 selected outbred Sprague-Dawley rats which differed in the extent of serum protein binding of this drug. In addition, the serum protein binding of phenprocoumon was altered in inbred Lewis rats by continuous treatment with tolbutamide. This drug was found to displace phenprocoumon from serum proteins without affecting its intrinsic clearance. The serum free fraction values (f_s)of the selected Sprague-Dawley rats ranged from 0.0053 to 0.0145. There were positive and linear correlations between f_s and the first-order elimination rate constant (k), f_s and total clearance (CL _total ),and f_s and the liver/plasma concentration ratio (L/P ratio) of phenprocoumon. The free fraction values in the liver tissue (f _I )showed twofold variations and were not related to f_s.The half-effective plasma concentrations (C _p50% )of total phenprocoumon (i.e., the concentrations necessary to inhibit the prothrombin complex synthesis rate by 50%) decreased with increasing f_s.The C_p50% values of total drug varied eightfold between the animals but those of free drug only 3.5- fold. The total anticoagulant effect per dose (AE/dose), as reflected by the magnitude of the area above the prothrombin complex activity vs. time curve in the plasma, varied only 1.5- fold between the rats and was not related to f_s.Continuous treatment of inbred Lewis rats with tolbutamide led to an increase of f_s (twofold), k (1.3-fold), V_d (1.5-fold), and CL_total (twofold). The intrinsic clearance (CL _intr )remained unaffected. There was no significant increase of f_L but a twofold increase of the L/P ratio. AE/dose and the C_p50% values of free drug in tolbutamide-treated rats were not significantly different from those of control rats. Thus an increase of the free fraction of phenprocoumon in the serum of rats is followed by a proportional increase of the total clearance. This prevents a concomitant rise of the free drug concentration. Consequently, the total anticoagulant effect per dose remains almost unaffected by about threefold variations in the serum free fraction values of this drug.This work was supported by the Deutsche Forschungsgemeinschaft: it is part of the Ph.D. thesis for D. T.     

Effect of ranitidine on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel

ABSTRACT

Objective: Clopidogrel is an oral thienopyridine antiplatelet agent indicated for the treatment of atherothrombotic events in patients with acute coronary syndrome (ACS). Prasugrel, a novel oral thienopyridine, is under investigation for the reduction of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. Prasugrel's solubility decreases with increasing pH, suggesting that concomitantly-administered medications that increase gastric pH may lower the rate and/or extent of prasugrel absorption. This study evaluated the influence of ranitidine coadministration on the pharmacokinetics and pharmacodynamics of the respective active metabolite of prasugrel and clopidogrel.

Research design and methods: In this open-label, two-period, two-treatment, crossover study, 47 healthy male subjects were randomized to one of two study arms, receiving either prasugrel (60-mg loading dose [LD], 10-mg maintenance dose [MD] for 7?days; n?=?23) or clopidogrel (600-mg LD, 75-mg MD for 7?days; n?=?24). In one treatment period, subjects received prasugrel or clopidogrel alone, and in the alternate period received the same thienopyridine with ranitidine (150?mg twice daily, starting 1?day before the LD). Pharmacokinetic parameter estimates (AUC_{0?t last}, C_max, and t_max) and inhibition of platelet aggregation (IPA) by light transmission aggregometry were assessed at multiple time points after the LD and final MD.

Results: Ranitidine had no clinically significant effect on the area under the plasma-concentration-time curve (AUC) and did not affect the time to C_max (t_max) for active metabolites of either prasugrel or clopidogrel. It reduced the geometric mean maximum concentrations of active metabolite (C_max) after a prasugrel and clopidogrel LD by 14% and 10%, respectively, but these differences were not statistically significant. When coadministered with a 60-mg prasugrel LD, ranitidine did not affect the time to, or magnitude of, peak IPA, but did result in a modest reduction at 0.5?h from 67.4 to 55.1% (p?<?0.001). Ranitidine did not affect prasugrel IPA during MD. For clopidogrel, IPA was not affected by ranitidine. Prasugrel and clopidogrel were both well-tolerated, with/without ranitidine.

Conclusions: Results from this study suggest that there is no significant drug–drug interaction between oral ranitidine therapy and concomitantly-administered prasugrel or clopidogrel.     

Effect of tramadol on metamizol pharmacokinetics and pharmacodynamics after single and repeated administrations in arthritic rats

Combined administration of certain doses of opioid compounds with a non-steroidal anti-inflammatory drug can produce additive or supra-additive effects while reducing unwanted effects. We have recently reported that co-administration of metamizol with tramadol produces antinociceptive effect potentiation, after acute treatment. However, none information about the effect produced by the combination after chronic or repeated dose administration exists. The aims of this study were to investigate whether the antinociceptive synergism produced by the combination of metamizol and tramadol (177.8 + 17.8 mg/kg, s.c. respectively) is maintained after repeated treatment and whether the effects observed are primarily due to pharmacodynamic interactions or may be related to pharmacokinetics changes. Administration of metamizol plus tramadol acute treatment significantly enhanced the antinociceptive effect of the drugs given alone (P < 0.05). Nevertheless, this effect decreased about 53% after the chronic treatment (3 doses per day, for 4 days). No pharmacokinetic interaction between metamizol and tramadol was found under acute treatment (P > 0.05). The mechanism involved in the synergism of the antinociceptive effect observed with the combination of metamizol and tramadol in single dose cannot be attributed to a pharmacokinetic interaction, and other pharmacodynamic interactions have to be considered. On the other hand, when metamizol and tramadol were co-administered under repeated administrations, a pharmacokinetic interaction and tolerance development occurred. Differences found in metamizol active metabolites’ pharmacokinetics (P < 0.05) were related to the development of tolerance produced by the combination after repeated doses. This work shows an additional preclinical support for the combination therapy. The clinical utility of this combination in a suitable dose range should be evaluated in future studies.     

Effects of water deprivation on the pharmacokinetics and pharmacodynamics of bumetanide in rats

The effects of temporary water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of bumetanide were examined after intravenous (i.v.) administration of bumetanide, 8 mg kg^?1 to control and water deprived rats (n = 7). The values of AUC, t_1/2 and MRT increased 79.0, 417, and 633 per cent, respectively, and CL and CL_NR decreased 44.0 and 41.2 per cent, respectively, in water deprived rats. They were all significantly different. The decreased CL_NR in water deprived rats could be due to decreased nonrenal metabolism of bumetanide; it could be supported that the amounts of glucuronide conjugate of bumetanide (52.5 vs 12.9 μg), desbutylbumetanide (170 vs 113 μg) and its glucuronide conjugation (191 vs 125 μg), and sum of the three metabolites (414 vs 229 μg), which are expressed in terms of bumetanide excreted in 24 h urine, decreased significantly in water deprived rats. The 8-h urine outputs per 100 g body weight (4.32 vs 1.34 ml) also reduced significantly in water deprived rats, and it might be due to significantly reduced amounts of bumetanide excreted in 8 h urine (90.9 vs 25.7 μg) and/or reduced kidney function in water deprived rats. The kidney function based on CL_lot (9.87 vs 2.14 ml min^?1 kg^?1) reduced significantly in water deprived rats. The 8-h urinary excretions of sodium (0.430 vs 0.0818 mmol), potassium (0.567 vs 0.270 mmol), and chloride (0.549 vs 0.0624 mmol) per 100 g body weight also reduced significantly in water deprived rats.