Pharmacokinetics of morphine are not altered in subjects with Gilbert's syndrome

AIMS: To verify that Gilbert's syndrome, which is caused by decreased glucuronidation capacity of the UDP-glucuronosyl transferase (UGT)1A1, does not account for impaired morphine clearance. METHODS: Noncompartmental pharmacokinetic parameters for morphine and its glucuronide metabolites were compared between five carriers of Gilbert's syndrome and six noncarriers after a 7.5 mg (19.8 micro mol) intravenous injection of morphine sulphate pentahydrate. To estimate the amount of morphine-6-glucuronide (M6G) formed from morphine, 1 mg of deuterized M6G was injected intravenously at the same time. RESULTS: No differences were detected between carriers and noncarriers of Gilbert's syndrome in the clearance of morphine (80.1 +/- 12 l h(-1) vs 87.9 +/- 22 l h(-1)) and in the percentage of morphine that was metabolized to M6G (10.9 +/- 1.4 vs 13 +/- 2). The areas under the plasma concentration vs time curves of morphine, M6G and morphine-3-glucuronide also did not differ between carriers and noncarriers of Gilbert's syndrome. CONCLUSIONS: Gilbert's syndrome is not a factor to be considered when prescribing morphine.     

氢核磁共振波谱法测定复方对乙酰氨基酚片中阿司匹林、咖啡因和对乙酰氨基酚

目的建立复方对乙酰氨基酚片中阿司匹林、咖啡因和对乙酰氨基酚测定的氢核磁共振波谱方法。方法采用氘代甲醇为溶剂,马来酸为内标。采用zg30脉冲序列获取~1H-NMR谱图。测试温度:300 K;谱宽:8 012 Hz;采集时间:4.01 s:弛豫时间:20 s,样品扫描次数:64次;空扫次数:2次。并采用HPLC法测定进行比较。结果阿司匹林、对乙酰氨基酚和咖啡因平均回收率分别为101.29%、101.68%、99.13%,RSD值分别为1.15%、1.73%、1.92%。qNMR法测定结果与HPLC法测定结果基本一致。结论氢核磁共振波谱法操作简便、快速,能准确测定复方对乙酰氨基酚片中阿司匹林、咖啡因和对乙酰氨基酚。     

Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia

AIMS

The major objective of the present study was to investigate the effect of imatinib on the pharmacokinetics of paracetamol in patients with chronic myelogenous leukaemia (CML).

METHODS

Patients (n= 12) received a single oral dose of acetaminophen 1000 mg on day 1 (control). On days 2–8, imatinib 400 mg was administered daily. On day 8 (treatment), another 1000 mg dose of paracetamol was administered 1 h after the morning dose of imatinib 400 mg. Blood and urine samples were collected for bioanalytical analyses.

RESULTS

The area under the plasma concentration–time curve (AUC) for paracetamol, paracetamol glucuronide and paracetamol sulphate under control conditions was similar to that after treatment with imatinib; the 90% confidence interval of the log AUC ratio was within 0.8 to 1.25. Urinary excretion of paracetamol, paracetamol glucuronide and paracetamol sulphate was also unaffected by imatinib. The pharmacokinetics of paracetamol and imatinib in Korean patients with CML were similar to previous pharmacokinetic results in white patients with CML. Co-administration of a single dose of paracetamol and multiple doses of imatinib was well tolerated and safety profiles were similar to those of either drug alone.

CONCLUSIONS

The pharmacokinetics of paracetamol and its major metabolites in the presence of imatinib were similar to those of the control conditions and the combination was well tolerated. These findings suggest that imatinib can be safely administered with paracetamol without dose adjustment of either drug.     

Influence of probenecid and paracetamol (acetaminophen) on zidovudine glucuronidation in human liver in vitro.

The effects of probenecid and paracetamol on zidovudine glucuronidation were investigated, in vitro, using human liver microsomal preparations. The presence of probenecid in the incubation medium significantly reduced the maximum reaction velocity for zidovudine glucuronide formation by more than 60 per cent, and the Km was reduced by 47 per cent, suggesting an uncompetitive inhibition of zidovudine glucuronidation. In contrast, paracetamol had no significant effect on zidovudine glucuronidation. The maximum reaction velocity for zidovudine glucuronide formation and the Km were unchanged when paracetamol (5 mM) was present in the incubation medium. The effects of probenecid and paracetamol on zidovudine metabolism in vitro correlates closely with those observed in vivo. The in vitro system of human liver microsomes may have a useful role in predicting the possible interaction of other drugs with zidovudine metabolism.     

Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration

Summary Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol levels declined multiphasically with a mean clearance after intravenous administration of 352±40 ml/min. A two-compartment open model appeared to describe the decline adequately. Comparison of the areas under the plasma concentration-time curves (AUC) indicated that oral bioavailability increased from 0.63±0.02 after 500 mg, to 0.89±0.04 and 0.87±0.08 after 1000 mg and 2000 mg, respectively. As a consequence of the incomplete bioavailability of paracetamol, as well as its multicompartmental distribution, accurate estimates of its distribution volume and clearance cannot be obtained if the drug is given orally. However, an estimate of its total plasma clearance may be derived from the AUC after a 500 mg oral dose.     

Paracetamol pharmacokinetics during the first trimester of human pregnancy

Paracetamol pharmacokinetics was evaluated in groups of pregnant (8–12 weeks) and non pregnant women given the standard oral dose of 650 mg.The mean half-life was significantly lower and oral clearance was significantly higher in the first trimester group compared to the control group. The AUC was lower in the first trimester but the difference was not significant. The maximum serum concentration (C_max) was reached 48 min after administration in both groups, and the mean maximal serum concentration was similar in the pregnant and non-pregnant women (11.16 and 11.58 g·ml^–1). A correlation of r=0.85 was found between C_max and the weight of the pregnant women (P<0.01) but not with the weight of the control women, this suggests that weight gain might be used to determine the women in whom dosage adjustment is needed.     

Paracetamol disposition in Thai patients during and after treatment of falciparum malaria

Investigations in animals have suggested that conjugation of paracetamol may be reduced in malaria. We have measured plasma concentrations and the urinary excretion of paracetamol and its phase II metabolites in eight Thai patients during uncomplicated falciparum malaria and in convalescence, following a 1000 mg single oral dose.The apparent oral clearance (Malaria, 3.6; Convalescence, 3.9; ml·min^–1·kg^–1), the elimination half-life (Malaria, 3.8; Convalescence, 3.7 h) and apparent volume of distribution (Malaria, 1.2; Convalescence, 1.2; l·kg^–1) of paracetamol were similar during malaria and convalescence. In addition, the urinary excretion of paracetamol and its major phase II metabolites and their formation clearances from paracetamol were not significantly different between the two study phases.These data show that clinical malaria infection has no effect on the conjugation of paracetamol in man.     

Paracetamol (acetaminophen) esters of some non-steroidal anti-inflammatory carboxylic acids as mutual prodrugs with improved therapeutic index

Paracetamol (acetaminophen) esters [4a-f] of some acidic NSAIDs were synthesized and evaluated as mutual prodrug forms with the aim of improving the therapeutic index through prevention of the gastrointestinal toxicity. The structures of the synthesized esters were confirmed by IR and ¹H-NMR spectroscopy and their purity was established by elemental analyses and TLC. In-vitro stability studies revealed that the synthesized ester prodrugs 4a-f are sufficiently chemically stable in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3 (t _1/2 ∼ 15–45 h)) and in phosphate buffer of pH 7.4 (t _1/2 ∼ 4–40 h). In 80% human plasma and 10% rat liver homogenate, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis releasing the corresponding NSAID and paracetamol at relatively faster rates (t _1/2 ≈ 15–385 min and 1–140 min, respectively). Calculated log P values indicated that the prodrugs 4a-f are more lipophilic than the parent drugs. In-vivo experiments in rabbits showed higher plasma levels of ibuprofen after oral administration of its ester prodrug 4b compared with those resulting from an equivalent amount of the corresponding physical mixture. Moreover, significant improvement in latency of pain threshold in mice has been observed up to 4 h after po administration of 0.02 mmol/kg of the prodrugs, compared with the corresponding physical mixtures. Gross observations and scanning electromicrographs of the stomach showed that the prodrugs induced very little irritancy in the gastric mucosa of mice after oral administration for 4 days. These results suggest that the synthesized mutual ester prodrugs were characterized by a better therapeutic index than the parent drugs.     

Paracetamol disposition and metabolite kinetics in patients with chronic renal failure

Summary The disposition of paracetamol following an oral dose of 1.0 g was compared in 10 healthy volunteers, 7 patients with moderate chronic renal failure and 6 patients with end stage renal failure on maintenance haemodialysis.Paracetamol absorption was normal in the patients with renal failure. The mean plasma half-life of paracetamol from 2 to 8 h was similar in the 3 groups (2.1 to 2.3 h) but from 8 to 24 h it disappeared much more slowly in the renal failure patients (half-life 11.7 compared with 4.9 h in the healthy volunteers). Plasma concentrations of paracetamol glucuronide and sulphate conjugates were greatly increased in the patients with moderate renal failure and the mean plasma half-lives were 30.5 and 21.8 h respectively compared with about 3 h in the healthy volunteers. Plasma concentrations of these metabolites were even higher in the dialysis patients and there was no significant fall over 24 h. The cysteine and mercapturic acid conjugates of paracetamol could only be measured in plasma in the patients with renal failure and concentrations were very low.The fractional urinary recovery of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates was similar in healthy volunteers and patients with moderate renal failure. The mean renal clearances of paracetamol and its glucuronide and sulphate conjugates in the healthy volunteers and patients with moderate renal failure were 15.7, 137 and 172, and 5.9, 14.5 and 14.8 ml/min respectively. In the latter patients the mean renal clearances of the cysteine and mercapturic acid conjugates were much greater at 35.4 and 80.2 ml/min. In the patients with moderate renal failure the AUC's of the glucuronide and sulphate conjugates were related to the plasma creatinine and there were significant negative correlations with the renal clearances of these metabolites and total urinary recovery. Marked cumulation of the polar glucuronide and sulphate conjugates of paracetamol would seem inevitable in patients with renal failure and the parent drug is apparently regenerated to a limited extent from retained metabolites.     

An expanded model of bilirubin kinetics: Effect of feeding,fasting, and phenobarbital in Gilbert's syndrome

In a patient with classical Gilbert's syndrome, tracer ¹⁴C-bilirubin was infused intravenously at constant rate for 20–32 hr. Total bilirubin production (TBrP) and bilirubin production as estimated from plasma data only (PBrP) were calculated from the specific activity of bilirubin in hepatic bile and in plasma. Pulse labeling with ³ H --aminolevulinic acid permitted estimation of bilirubin fractions synthesized in the liver and excreted directly into bile or returned to plasma. Neither fasting nor phenobarbital (PB) affected TBrP or PBrP; the rise in plasma bilirubin on fasting and fall on PB were entirely accounted for by changes in hepatic pigment clearance. A multicompartmental model, formulated to fit the data obtained in all three experimental conditions, suggested that bilirubin produced in hepatocytes is characterized by three discrete, noncommunicating compartments which differ kinetically and in the manner of pigment transport into plasma, bile, or both. The size and kinetics of each hepatic compartment resembled those of known hepatic heme or hemoprotein fractions. Transfer of bilirubin from plasma to bile occurs by separate hepatic channels which do not communicate in the liver with compartments of endogenously formed pigment. Fasting and PB produced minor modifications in mass and turnover of individual hepatic compartments but did not significantly alter the total rate of bilirubin synthesized in the liver and delivered either to plasma or directly into bile. These findings suggest that production and transport of bilirubin in the liver are highly compartmentized processes.This investigation was supported in part by Grant AM-11275 from the National Institutes of Health, the Walter C. Pew Fund for Gastrointestinal Research, and General Clinical Research Center Grant RR-00079. G.K. is a USPHS Research Trainee (Grant GM-2019). D.M.S. is the recipient of USPHS Research Career Development Award GM-70304.     

苯巴比妥钠对小鼠醋氨酚代谢的影响

目的研究小鼠醋氨酚（Ａｃｅ）的有关药代动力学及苯巴比妥钠（Ｐｈｅ）对其的影响。方法给正常小鼠和Ｐｈｅ５０ｍｇ·ｋｇ－１ｉｐ７ｄ的小鼠,尾静脉注射Ａｃｅ１００ｍｇ·ｋｇ－１,用ＨＰＬＣ法测定血浆Ａｃｅ及尿液Ａｃｅ、葡萄糖醛酸—Ａｃｅ（ＧＡ）和硫酸—Ａｃｅ（ＳＡ）含量,计算机自动曲线拟合,计算比较其有关药代动力学参数及尿液代谢产物累积排泄量。结果小鼠Ａｃｅ血浆浓度量－时关系曲线呈一房室模型,Ｔ１２为１３．９±０．５５ｍｉｎ,ＣＬ为（０．０４０３２±０．００３８２）Ｌ·ｋｇ－１·ｍｉｎ－１,９ｈ尿液Ａｃｅ、ＧＡ和ＳＡ总累积排泄量为给药量的５４．０％±６．２１％。经Ｐｈｅ诱导后,ＡｃｅＴ１２缩短２７．７％,ＣＬ增加２５．２％,尿液ＧＡ减少１９．３％（Ｐ＜０．０５）。结论至少在ＩＣＲ和昆明种小鼠,Ａｃｅ除与葡萄糖醛酸和硫酸结合外,还有其它重要代谢途径。Ｐｈｅ预处理明显加快小鼠血浆Ａｃｅ消除,但该作用与葡萄糖醛酸和硫酸结合代谢反应无关。     

对乙酰氨基酚口腔崩解片人体药动学和生物等效性评价

目的:评价对乙酰氨基酚口腔崩解片的生物等效性。方法:按照随机交叉自身对照,19例男性健康受试者单剂量口服对乙酰氨基酚口腔崩解片(受试制剂)、对乙酰氨基酚片(商品名:必理通,参比制剂)各500 mg后,血浆样品经液-液萃取后,采用高效液相色谱法测定浓度,计算药动学参数,进行人体相对生物利用度及生物等效性研究。结果:受试制剂和参比制剂的C_(max)分别为(9．71±2．78)和(10．35±3．86)mg·L～(-1),T_(max)分别为(0．82±0．45)和(0．74±0．67)h,t_(1/2)分别为(2．90±0．42)和(3．13±0．67)h,AUC_(0-1)分别为(30．79±7．97)和(31．44±7．06)mg·h·L～(-1),主要药动学参数之间均无显著性差异。试验片的平均相对生物利用度为(108．28±18．83)%。结论:受试制剂和参比制剂为生物等效。     

Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

Aims Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2  h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Methods Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40  mg  kg⁻¹ were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70  kg person using an allometric power model.
Results Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2  l  h⁻¹ (CV 47%), volume of distribution 67.1  l (CV 58%) and absorption rate constant 0.77  h⁻¹ (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72  h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Conclusions Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2  h before anticipated pain or fever in children.     

Induction of an ATPase inhibitor protein by propylthiouracil and protection against paracetamol (acetaminophen) hepatotoxicity in the rat

1. The purpose of the present study was to test the following hypothesis: propylthiouracil (PTU) treatments of rats induces an increase in the concentration and activity of the mitochondrial ATPase (m-ATPase) inhibitor protein (IF₁). The PTU-induced elevated baseline levels of this inhibitor protein inactivated m-ATPase, and prevented hepatotoxicity by a toxic dose of acetaminophen (AAP) (paracetamol), by maintaining hepatic adenosine 5′-triphosphate (ATP) levels.
2. Male Wistar rats were either gavaged with a toxic dose of AAP alone, or after pretreatment with PTU for periods of 3 and 12 days.
3. Twenty four hours after acetaminophen treatment alone, toxicity was manifested by: an approximately 10 fold increase in serum transaminase levels (serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase); depletion of hepatic reduced glutathione (GSH) and ATP levels; loss of inhibitor protein activity, and extensive pericentral necrosis of the hepatocytes. Propylthiouracil pretreatment for 12 days enhanced the concentration of the following metabolites in the liver: ATP (1.5 fold), ATPase inhibitor protein (IF₁) (4.5 fold), and reduced glutathione (1.3 fold), while the activity of the inhibitor protein increased 2 fold. When the PTU treated rats were challenged with AAP, transaminases were not elevated, and only sporadic areas of necrosis were detected by histological examination of the liver tissue. In contrast to the 12 day treatment with PTU the 3 day treatment had no protection against AAP. No histological evidence of protection was manifested and the transaminases were not different from AAP treated controls. Most of the protective metabolites were depleted.
4. Our findings suggest that PTU-induced increased concentration of inhibitor protein and GSH, are contributing factors in the prevention of hepatotoxicity by maintaining hepatic m-ATP levels and reducing the harmful effect of the toxic metabolite of AAP.

     

HPLC法测定外用对乙酰氨基酚凝胶中对乙酰氨基酚的含量

目的:建立外用对乙酰氨基酚凝胶中对乙酰氨基酚的HPLC含量测定方法.方法:选用YMC-C18(150×4.6mm,5μm)色谱柱,流动相为甲醇-水-磷酸(22:78:0.1),检测波长为250nm,流速为1.0mL·min-1.结果: 对乙酰氨基酚的量在0.04μg～0.14μg内与峰面积呈良好线性关系,相关系数r=0.9996,平均回收率为99.72%,RSD为0.73%.结论:方法操作简便,准确,灵敏度高,为外用对乙酰氨基酚凝胶质量控制提供了定量依据.     

RP-HPLC测定对乙酰氨基酚缓释片中对乙酰氨基酚的含量

目的建立反向高效液相色谱法测定对乙酰氨基酚缓释片中对乙酰氨基酚的含量。方法用HYPERS IL ODS-C18柱(4.6mm×250mm,5μm),以甲醇-水(52∶48)为流动相,流速1.0mL.m in-1,检测波长为254nm,采用标准曲线法。结果对乙酰氨基酚在2.04μg.mL-1~20.40μg.mL-1浓度范围有良好线性关系,r=0.9999,平均回收率为100.06%,RSD为2.30%(n=9)。结论该方法简便、准确、灵敏、重现性良好,适用于对乙酰氨基酚缓释片中对乙酰氨基酚的含量测定。     

Paracetamol [acetaminophen]-induced gastrotoxicity: revealed by induced hyperacidity in combination with acute or chronic inflammation

Paracetamol is regarded as a relatively safe drug in the gastro-duodenal region of humans but recent epidemiological investigations have suggested that at high doses there may be an increased risk of ulcers and bleeding. To investigate the possibility that inflammatory conditions and gastric acidity may play a role in potentiating development of gastric mucosal injury from paracetamol in rats (as noted previously with various non-steroidal anti-inflammatory drugs) we studied the gastric irritant effects of paracetamol and some phenolic and non-phenolic analgesics and antipyretics in rats with adjuvant or collagen II induced arthritis or zymosan-induced paw inflammation and given 1.0 ml hydrochloric acid (HCl) 0.1 M and/or an i. p. injection of the cholinomimetic, acetyl-β-methyl choline chloride 5.0 mg/kg. Gastric lesions were determined 2 h after oral administration of 100 or 250 mg/kg paracetamol or at therapeutically effective doses of the phenolic or non-phenolic analgesics/antipyretics. The results showed that gastric mucosal injury occurred with all these agents when given to animals that received all treatments so indicating there is an adverse synergy of these three factors, namely: (i) intrinsic disease; (ii) hyperacidity; and (iii) vagal stimulation for rapidly promoting gastric damage, both in the fundic as well as the antral mucosa, for producing gastric damage by paracetamol, as well as the other agents. Removing one of these three predisposing factors effectively blunts/abolishes expression of this paracetamol-induced gastrotoxity in rats. These three factors, without paracetamol, did not cause significant acute gastropathy. Received 4 February 2004; revised 9 January 2006; accepted 24 February 2006     

氨酚帕马溴片健康人体药动学

目的:研究氨酚帕马溴片在健康人体单、多次给药的药动学。方法:30名健康女性志愿者,随机平均分为3组,单次给药分别口服氨酚帕马溴片1片(含对乙酰氨基酚500mg、帕马溴25mg)、2片、3片,单次给药采血结束,中剂量组继续给药,每次2片,q8h×6d。按试验方案采血,高效液相色谱法同时测定血清中对乙酰氨基酚和8-溴茶碱浓度,DAS2.0软件计算药动学参数。结果:健康受试者单次给药后各组对乙酰氨基酚的主要药动学参数tmax分别为(0.75±0.17),(1.2±0.7),(0.9±0.4)h;Cmax分别为(10.0±1.5),(22.4±6.9),(26.6±5.0)mg.L-1;MRT0-48h分别为(3.5±0.3),(3.5±0.8),(3.6±0.4)h;AUC0-48h分别为(37.5±4.2),(72.3±10.2),(105.8±16.0)mg.h.L-1;8-溴茶碱的主要药动学参数tmax分别为(0.78±0.14),(1.4±1.0),(0.90±0.27)h;Cmax分别为(2.5±0.4),(5.2±1.1),(6.2±0.6)mg.L-1;MRT0-48h分别为(12.0±2.7),(1...     

The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage

Summary Seventeen patients received standard treatment with intravenous N-acetylcysteine for 18 episodes of severe poisoning with paracetamol (acetaminophen). The dose of N-acetylcysteine was 150 mg/kg given in 15 min followed by 50 mg/kg in 4 h and 100 mg/kg over the next 16 h. Liver damage was absent or mild on 13 occasions (ALT<500 µ/l) and severe on 5 (ALT>1000 µ/l).Total plasma N-acetylcysteine was estimated by HPLC. The mean maximum plasma concentration after the initial loading dose was 554 mg/l. Concentrations then fell rapidly and after 12 h a mean steady-state level of about 35 mg/l was maintained. When the infusion was discontinued N-acetylcysteine disappeared with a half-life of 5.7 h. The mean steady-state volume of distribution, AUC, mean residence time and total clearance were 536 ml/kg, 1748 mg·h·l^–1, 2.91 h and 3.18 ml·min^–1·kg^–1. These values are generally consistent with those previously reported with much smaller doses and the disposition of N-acetylcysteine does not appear to be dose-dependent. The elimination of N-acetylcysteine was not impaired in the patients with severe liver damage, and the pharmacokinetic variables and plasma concentrations were similar in patients with and without hepatotoxicity.The dosage schedule for intravenous N-acetylcysteine should probably be modified since adverse reactions invariably occur early when plasma concentrations are at their highest, and liver damage was prevented just as effectively at the lowest as at the highest C_max. High initial concentrations of N-acetylcysteine can be avoided with simple alternative regimens based on the kinetic data of this study.