A study of the relative hepatotoxicity in vitro of the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen and butibufen

1. The cytotoxic and metabolic effects of ibuprofen, flurbiprofen and butibufen have been studied in primary cultured hepatocytes. Toxic effects were observed for all three drugs at 10 times the therapeutic plasma concentration. 2. None of the drugs affected cell survival after 48 h of continuous exposure at their therapeutic plasma concentration, although significant increases of LDH leakage were detected. 3. Ibuprofen and butibufen were the most active in impairing gluconeogenesis from lactate (88% and 76% inhibition respectively) after 6 h exposure at therapeutic plasma concentrations. 4. At 5 times therapeutic plasma concentrations, albumin synthesis was inhibited 40% (ibuprofen), 35% (flurbiprofen) and 100% (butibufen) after 6 h exposure and significant effects were also observed after 24 h exposure. 5. Urea synthesis was inhibited 11% by butibufen at its therapeutic plasma concentration but only at higher concentrations by the other drugs. 6. Butibufen was potentially the most hepatotoxic drug as it has the highest therapeutic plasma concentration and had the lowest margin between therapeutic and toxic concentrations.     

A study of the relative hepatotoxicity in vitro of the non-steroidal anti-inflammatory drugs ibuprofen,flurbiprofen and butibufen

1. The cytotoxic and metabolic effects of ibuprofen, flurbiprofen and butibufen have been studied in primary cultured hepatocytes. Toxic effects were observed for all three drugs at 10 times the therapeutic plasma concentration.

2. None of the drugs affected cell survival after 48 h of continuous exposure at their therapeutic plasma concentration, although significant increases of LDH leakage were detected.

3. Ibuprofen and butibufen were the most active in impairing gluconeogenesis from lactate (88% and 76% inhibition respectively) after 6h exposure at therapeutic plasma concentrations.

4. At 5 times therapeutic plasma concentrations, albumin synthesis was inhibited 40% (ibuprofen), 35% (flurbiprofen) and 100% (butibufen) after 6h exposure and significant effects were also observed after 24 h exposure.

5. Urea synthesis was inhibited 11% by butibufen at its therapeutic plasma concentration but only at higher concentrations by the other drugs.

6. Butibufen was potentially the most hepatotoxic drug as it has the highest therapeutic plasma concentration and had the lowest margin between therapeutic aiid toxic concentrations.     

Vasomodulation Influences on the Transdermal Delivery of Ibuprofen

The purpose of the study was to evaluate the effect of adding peripheral vasodilators, tolazoline, or papaverine, to transdermal drug delivery vehicles with the goal of improving the tissue bioavailability of transdermally delivered ibuprofen. Ibuprofen (150 mg) formulations with several concentrations of two different vasodilators and/or a penetration enhancer (PE) complex were topically applied to rabbits. Plasma levels of ibuprofen were determined by a validated high-performance liquid chromatography method and evaluated at 0, 0.5, 1, 2, and 3 h. The PE complex enhanced the plasma ibuprofen level approximately sevenfold versus control, and tolazoline (0.005%) added to the PE complex increased the plasma levels of ibuprofen approximately another twofold compared with the PE. Higher concentrations of tolazoline paradoxically did not exhibit vasodilator enhancement to ibuprofen delivery. Papaverine was tested in the same manner. In this set of experiments, PE increased the plasma ibuprofen 3.7-fold versus control, and addition of papaverine (0.0005%) increased plasma ibuprofen an additional 3.3-fold compared with the PE formulation. Transdermal formulations of ibuprofen containing low concentrations of tolazoline or papaverine increased plasma ibuprofen levels in the presence of passive PE components.     

Pharmacokinetics of trazodone and its major metabolite m-chlorophenylpiperazine in plasma and brain of rats

Sprague-Dawley rats were used as models for single trazodone administration (males), continuous adminstration and dose proportionality experiments (males, females, pregnant females). Plasma and brain tissue were analysed for trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP). Fetal exposure to trazodone and m-CPP was assessed and differences in their steady-state plasma concentration were sought between adult males and females. Both trazodone and m-CPP rapidly appeared in plasma and brain tissue following a single intraperitoneal trazodone dose with brain concentrations exceeding those in plasma. Plasma concentrations of m-CPP were lower than those of trazodone but exceeded them in brain tissue. Chronic administration using osmotic mini-pumps revealed a significant linear relationship between trazodone concentration in plasma and brain at steady-state (r=0.96, p<0.0001). No simple relationship was found between plasma and brain tissue concentration for m-CPP. In contrast to observations following single trazodone administration, m-CPP concentrations at steady-state were lower than trazodone concentrations in brain tissue, suggesting a lack of stationarity in the disposition of trazodone over time. No significant differences in plasma or brain tissue drug concentrations relative to administered trazodone dose were observed between male and female rats, nor between pregnant and non-pregnant females. Trazodone and m-CPP were both detected in fetal and placental tissues, with placenta having the highest concentrations. The data suggest that neuropharmacological studies of trazodone could yield different results depending upon the route and schedule of drug administration. Maternally administered trazodone, like many other antidepressants, is distributed to fetal tissues in rodents, reaffirming the need for caution in treating pregnant women with psychoactive drugs.     

Ibuprofen suppresses interleukin-1beta induction of pro-amyloidogenic alpha1-antichymotrypsin to ameliorate beta-amyloid (Abeta) pathology in Alzheimer's models.

Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Abeta) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Abeta production has not been ruled out. We show that ibuprofen reduced Abeta brain levels in rats from exogenously infused Abeta in the absence of altered Abeta production. To determine whether ibuprofen inhibits pro-amyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Abeta and inflammation-related molecules alpha1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor gamma) (PPARgamma) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1beta, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Abeta42 production, these observations suggest that ibuprofen reduction of Abeta pathology may not be mediated by altered Abeta42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1beta and its downstream target ACT).     

Pharmacokinetics of oral ibuprofen in premature infants

Patent ductus arteriosus (PDA) is a frequent complication in premature infants. So far, intravenous indomethacin is the standard mode of medical therapy in such patients but carries a risk of frequently occurring side effects. Ibuprofen, another nonsteroidal anti-inflammatory drug, has also been shown to be efficacious in closing ductus with lesser adverse effects after parenteral administration. However, limited data are available on the pharmacokinetics of intravenous ibuprofen in this population. Nonavailability of parenteral preparation and lack of information regarding pharmacokinetic disposition of ibuprofen in this subgroup of the population led the authors to conduct this pharmacokinetic study with oral ibuprofen. Twenty premature infants with a gestational age of 30.45 +/- 0.33 weeks and a birth weight of 1262.5 +/- 55.4 g (values given as mean +/- SEM) admitted to the neonatal unit were enrolled in this study. Ibuprofen was administered in a single oral dose of 10 mg/kg between 4 and 72 hours postnatally, and blood samples were collected through an indwelling vascular catheter at time 0 and 1, 2, 4, 8, 12, and 24 hours. Ibuprofen plasma concentrations were assayed by high-performance liquid chromatography. There was a large interindividual variability observed for plasma concentrations, elimination half-life (t1/2) (15.72 +/- 3.76 h), and area under the plasma concentration-time curve (AUC0-infinity) (402.60 +/- 79.67 micrograms.h/mL) in these babies. Variables such as gestational age, birth weight, and sex did not affect ibuprofen pharmacokinetics significantly (p > 0.05). Moreover, no correlation could be found between elimination half-life and gestational age (r = 0.02). Ibuprofen pharmacokinetics showed a wide variability in premature infants. The results of the present study warrant revising the oral dosage schedule to achieve comparable plasma concentrations of ibuprofen associated with successful closure of ductus, as reported in earlier studies.     

Dual-targeting for brain-specific drug delivery: synthesis and biological evaluation

Ibuprofen is one of the most potent non-steroid anti-inflammatory drugs (NSAIDs) and plays an important role in the treatment of neurodegenerative diseases. However, its poor brain penetration and serious side effects at therapeutic doses, has hindered its further application. Thus, it is of great interest to develop a carrier-mediated transporter (CMT) system that is capable of more efficiently delivering ibuprofen into the brain at smaller doses to treat neurodegenerative diseases. In this study, a dual-mediated ibuprofen prodrug modified by glucose (Glu) and vitamin C (Vc) for central nervous system (CNS) drug delivery was designed and synthesized in order to effectively deliver ibuprofen to brain. Ibuprofen could be released from the prepared prodrugs when incubated with various buffers, mice plasma and brain homogenate. Also, the prodrug showed superior neuroprotective effect in vitro and in vivo than ibuprofen. Our results suggest that chemical modification of therapeutics with warheads of glucose and Vc represents a promising and efficient strategy for the development of brain-targeting prodrugs by utilizing the endogenous transportation mechanism of the warheads.     

Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics

Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen.     

Synthesis,in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery

New glycosyl derivatives of ibuprofen (I, II, III, and IV) were synthesized in order to overcome the ineffective delivery of ibuprofen across the blood–brain barrier owing to its low permeability, using d-glucose as a drug targeting agent. Ibuprofen was linked directly to the C-2, C-3, C-4, and C-6 positions of glucose via ester bonds. Furthermore, in vitro stabilities of the four ester derivatives were evaluated to determine both their stability in aqueous medium and their feasibility to undergo enzymatic cleavage by esterase in biological samples to regenerate the original drug. From the obtained results, compounds I–IV appeared to be moderately stable in pH 7.43 buffer solution, rat plasma, and brain tissue extracts. In vivo experiments showed that the AUC_0–t of ibuprofen in plasma after the injection of prodrugs is several times higher than that of AUC_0–t after the injection of ibuprofen. In addition, the maximal concentration of ibuprofen in brain after the administration of ester IV was three fold higher than that of the control group. Also, the concentration of ibuprofen was kept stable in brain for about 4?h for four esters, which was beneficial for the treatment of Alzheimer’s disease and highlighted the possibility of brain drug delivery of ibuprofen using prodrug strategies.     

Antiulcer activities of liquorice and its derivatives in experimental gastric lesion induced by ibuprofen in rats

Ibuprofen is a clinically important non-steroidal anti-inflammatory analgesic and antipyretic drug widely used in the treatment of several forms of arthritis and for mild to moderate pain. Analogously to other aspirin-like drugs, ibuprofen irritates the gastric mucosa and liquorice extracts have long been used to treat peptic ulcers. In this study we examined the protective effect of liquorice or its derivatives against gastric ulcers induced by oral ibuprofen. A granular mixture of ibuprofen alone or coated with liquorice or its derivatives including deglycyrrhized liquorice (DGL), highly glycyrrhized liquorice (HGL), enoxolone (glycyrrhetinic acid) and carbenoxolone, were studied. Ibuprofen coated with liquorice, DGL or enoxolone reduced the number and size of ulcers, lowering the ulcer index from 1.86 to 1 and the incidence from 100 to 59%. Coating with other derivatives was less effective. Plasma concentrations of ibuprofen were determined by high-performance liquid chromatography (HPLC), and showed that ibuprofen absorption was not affected by liquorice or its derivatives.     

布洛芬丁香酚酯前体药物的合成及其水解动力学

目的合成布洛芬丁香酚酯并研究其在不同pH水溶液中及血浆、肝匀浆中的水解动力学。方法以布洛芬和丁香酚为原料,经过酯化反应合成了布洛芬前体药物布洛芬丁香酚酯,利用HPLC法测定不同pH值的缓冲溶液、血浆及肝均浆中药物水解动力学。经UV、IR、MS和NMR确证了目标化合物的结构。结果布洛芬丁香酚酯在pH为1.10~9.96时水解速率常数不受pH影响,pH为10.91~11.91时随pH值增加水解速率增大;在血浆及肝均浆中布洛芬丁香酚酯可迅速水解成布洛芬和丁香酚。结论布洛芬丁香酚酯是一个具有良好前景的非甾体抗炎前体药物。     

Effects of age and dose on the pharmacokinetics of ibuprofen in the rat.

The pharmacokinetics of ibuprofen after 2.5 and 25 mg/kg doses were examined in young adult (5 months) and senescent (24 months) male Fischer 344 rats. Plasma concentrations of ibuprofen were determined by HPLC and protein binding was measured by equilibrium dialysis. The cytochrome P-450-mediated metabolism of ibuprofen was investigated in vitro using microsomal protein from rat liver as the source of drug-metabolizing enzymes. Dose had a marked effect on the disposition of ibuprofen, with free plasma clearance (CLfree) decreasing 40% and apparent free steady-state volume of distribution (Vssfree) decreasing 58% as dose increased from 2.5 to 25 mg/kg. These changes reflected saturation of elimination pathways and tissue-binding sites. The binding of ibuprofen to plasma proteins was dependent on drug concentration. Unlike the parameters based on free ibuprofen concentrations, there were no significant changes in total plasma clearance (CL) or steady-state volume of distribution (Vss) due to the nonlinear protein binding. Aging also had a significant effect on ibuprofen pharmacokinetics. Decreases in CLfree and Vssfree of 42 and 51%, respectively, suggested a reduction in metabolic activity and binding of ibuprofen to tissue components in the aged rats. A decrease in plasma protein binding in the old rats was related to decreases in albumin concentration and the number of albumin binding sites. Thus, due to the greater free fraction of ibuprofen in the plasma of aged rats, CL increased significantly, whereas Vss remained unaffected by age when total plasma concentrations were examined. The metabolic capacity exhibited an age-related decline of 42%, whereas the affinity of the metabolic enzymes for ibuprofen was unaffected by age.     

单剂量和多剂量口服布洛伪麻那敏干混悬剂在健康人体的药代动力学

目的研究布洛伪麻那敏干混悬剂(抗感冒药)在健康成年志愿者体内的药代动力学。方法3个单剂量组及1个多剂量组口服给药,用高效液相色谱-紫外检测法测定给药后不同时间布洛芬血药浓度,高效液相色谱-串联质谱法测定给药后不同时间伪麻黄碱和氯苯那敏血药浓度。用DAS Ver 2.0计算药代动力学参数并进行统计分析。结果3组单剂量及连续口服布洛芬(单剂:200,400,600 mg;连续:200 mg)、伪麻黄碱(单剂:30,60,90 mg;连续:30 mg)及氯苯那敏(单剂:2,4,6 mg;连续2 mg)7天后的主要药代动力学参数(tmax,Cmax,AUC0-t,AUC0-∞,t1/2等)结果显示,布洛芬、伪麻黄碱和氯苯那敏血药浓度-时间曲线拟合结果均符合一室模型,体内过程均呈线性动力学特征。结论连续多次给药,3组分都不存在药酶诱导或抑制现象。     

Rapid HPLC-determination of ibuprofen and flurbiprofen in plasma for therapeutic drug control and pharmacokinetic applications

Ibuprofen has wide applications in the treatment of rheumatoid arthritis and osteoarthroses as an effective non-steroidal antiinflammatory drug. The drug is still being investigated regarding its possible ability to reduce myocardial infarct size. The more potent biphenyl propionic analogue, flurbiprofen, has recently been introduced. Both drugs are strong inhibitors of cyclooxygenase. The specific HPLC-method described requires plasma samples of 100 microliter which are deproteinized and simultaneously extracted with acetonitrile containing either of the drugs as internal standard. Aliquots of 25 microliter of this primary extract were directly injected on a mu Bondapack C18 column. For elution was used a mixture of 60% methanol and 40% 50 mM phosphate buffer adjusted to pH 4.6. The detection limit (at 214 nm) for both drugs corresponded to plasma concentrations of about 0.2 micrograms X ml-1. The applicability of the method was demonstrated in a pharmacokinetic ibuprofen experiment in an adult person.     

Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemate

AIMS: To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects. METHODS: Sixteen healthy volunteers received cross-over ibuprofen lysinate as either one tablet of 400 mg ('test') or two tablets of 200 mg ('reference'). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R- to S-ibuprofen into account. RESULTS: Peak plasma concentrations of R- and S-ibuprofen were 18.1 and 20 microg ml(-1) (test), and 18.2 and 20 microg ml(-1) (reference). Areas under the plasma concentration vs. time curves were 39.7 and 67.5 microg ml(-1) h (test), and 41.1 and 68.2 microg ml(-1) h (reference). Clearance of R-ibuprofen was 5.2 (test) and 5 l h(-1) (reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R-and then for S-ibuprofen): body clearance: 4.9 and 4.64 l h(-1), central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h(-1), peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h(-1), and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation. CONCLUSIONS: Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen.     

Quantitative assessment of markers of inflammation,arthritis and pain in rats with adjuvant arthritis following the treatment with ibuprofen cream and placebo

When applied topically, nonsteroidal antiinflammatory drugs (NSAIDs) are absorbed locally and hence systemic adverse effects can be avoided due to very low plasma concentrations. In addition, direct local antiphlogistic treatment of the affected area is desirable. The present study was undertaken to assess markers of inflammation, arthritis and pain in rats with adjuvant arthritis undergoing treatment with ibuprofen cream (Dolgit cream) and placebo. Ibuprofen cream was applied (70 mg/hind paw) 3 times daily on hind paws from day 12 (after the initial signs of hind paw swelling appeared) for 3 weeks. Pain threshold, hind paw swelling, arthrogram score and serum albumin concentrations were measured in healthy controls, in rats with adjuvant arthritis and in rats treated with both placebo and active cream. Pain threshold increased in rats treated with ibuprofen cream (after 12 days of application), but this change was not significant. However, hind paw swelling significantly decreased as early as after 5 days of treatment with ibuprofen cream in comparison with both arthritic and placebo-treated rats and remained decreased throughout the study (an additional 16 days). Evaluation of the arthrogram score gave similar results. Serum albumin levels were unaffected by ibuprofen cream treatment. In conclusion, our results show that topical application of ibuprofen cream on inflamed hind paws produced significant local antiinflammatory and antiarthritic effects in rat adjuvant arthritis.     

Effect of nonsteroidal anti-inflammatory drugs on glycogenolysis in isolated hepatocytes.

E-series prostaglandins have previously been demonstrated to inhibit hormone-stimulated glycogenolysis when added to isolated hepatocytes of the rat. In the present study, the effect of nonsteroidal anti-inflammatory drugs, which inhibit cyclo-oxygenase activity, on glycogenolysis was examined in the hepatocyte model. Ibuprofen (80 microM), indomethacin (50 microM) and meclofenamate (60 microM) all increased rates of glycogenolysis when added under basal conditions. In contrast, piroxicam (50 microM) had no effect on glycogenolysis in the hepatocyte system. Concentrations of ibuprofen below 80 microM did not significantly increase rates of glycogenolysis. Ibuprofen (80 microM) had no effect on glycogenolysis in the presence of 10(-5)M adrenaline or 5 X 10(-7)M glucagon, but did increase glycogenolytic rates in the presence of 5 X 10(-8)M glucagon. Ibuprofen-stimulated glycogenolysis was inhibited by addition of prostaglandin E2 (PGE2). Under conditions where glucagon-stimulated glycogenolysis was inhibited by exogenous PGE2, addition of ibuprofen (80 microM) increased the rate of glycogenolysis. Ibuprofen had no effect on basal or glucagon-stimulated hepatocyte adenylate cyclase activity. In conclusion, these results demonstrate that nonsteroidal anti-inflammatory drugs which are carboxylic acids can increase the rate of glycogenolysis in isolated hepatocytes. The high concentrations of drug required to stimulate glycogenolysis, the lack of effect of piroxicam, and the demonstration of stimulation by ibuprofen in the presence of exogenous PGE2 all suggest that the stimulation of glycogenolysis by ibuprofen, indomethacin and meclofenamate is independent of cyclooxygenase inhibition. These observations are consistent with reports that carboxylic acid nonsteroidal anti-inflammatory drugs can interfere with hepatic intracellular calcium handling.     

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children.

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one-compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUCO----infinity) of ibuprofen 10 mg/kg were less than expected for a two-fold increase in dose. For acetaminophen, the tlag was less than ibuprofen, Ka was more than ibuprofen, and beta was less than ibuprofen. The ibuprofen beta was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUCO-----infinity was higher in the older (greater than or equal to 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUCO----infinity and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.     

精氨洛芬片剂与颗粒剂在健康受试者体内的生物等效性

目的 研究精氨洛芬(非甾体抗炎药)片剂与颗粒剂在中国健康志愿者体内的生物等效性.方法 20名健康男性受试者分别随机交叉口服精氨洛芬片(试验制剂)及其颗粒(参比制剂)0.4 g,用HPLC-UV法测定给药后不同时间点的血浆布洛芬浓度;用DAS程序对试验数据进行统计处理,评价2种制剂的生物等效性.结果 试验制剂和参比制剂的药代动力学参数如下:Cmax分别为(50.60±9.12)、(50.53±8.58)nag·L-1,tmax分别为(0.51±0.20)、(0.34±0.11)h,AUC0～t分别为(118.63±21.42)、(115.75±20.23)mg·h·L-1,AUC0～∞分别为(121.18±22.18)、(118.55±21.83)mg·h·L-1.试验制剂与参比制剂AUC0-t之比和Cmax之比的90%可信区间分别为97.5%～107.6%和93.3%～107.2%.结论 试验制剂和参比制剂吸收程度等效(AUC0-t,AUC0-∞和Cmax均生物等效性);但吸收速度不等效(tmax不等效).     

A double-blind, placebo controlled, cross-over comparison of the analgesic effect of ibuprofen 400 mg and 800 mg on laser-induced pain.

1. The analgesic efficacy of single oral doses (400 mg, 800 mg) of ibuprofen on argon laser-induced pain was studied in a double-blind, placebo controlled, three way cross-over comparison. Ten healthy volunteers participated. 2. Pain thresholds and plasma concentrations of the S- and R-enantiomers of ibuprofen were measured every hour up to 8 h after medication. 3. Ibuprofen (400 mg) produced an analgesic effect significantly superior (P less than 0.05) to placebo 1-4 h after medication. Ibuprofen (800 mg) was significantly superior to placebo 2-4 h after administration. No differences were found between 400 mg and 800 mg, when hourly threshold differences were compared. 4. Comparing total analgesic effect (area under effect curve), both active medications were superior to placebo (P less than 0.01-0.05), and 400 mg was superior to 800 mg (P less than 0.05). 5. Peak plasma concentrations of S- and R-ibuprofen occurred between 1.2 and 1.5 h. Concentrations after the 800 mg dose were higher than those after the 400 mg dose at all times.