重组嵌合抗CD20单抗PUM100单次给药药代动力学研究

目的:研究国产重组嵌合抗CD20单抗PUM100经静脉单次给药后在食蟹猴体内的药代动力学,与相同条件下利妥昔单抗的药代动力学参数进行比较,评价二者的生物等效性关系。方法:12只食蟹猴按体重均衡法分为4组,分别单次给予不同剂量(10,30 mg.kg-1)的PUM100和利妥昔单抗,在不同时间点采血分离血清,用ELISA法测定血清中药物浓度;根据非房室统计矩模型用WinNolin药代软件对测定结果进行曲线拟合并计算药代动力学参数。结果:食蟹猴经静脉推注单次给予不同剂量(10,30 mg.kg-1)的PUM100后,半衰期(t1/2)分别为(111.3±10.8)和(154.0±39.1)h,全身清除率(CL)与表观分布容积(Vss)较接近,C0及AUC0-inf与给药剂量正相关,且两个剂量对应时间点的血药浓度存在显著性差异;PUM100与等剂量利妥昔单抗的主要药代动力学参数无显著性差异。结论:PUM100与等剂量利妥昔单抗的血清药物浓度-时间曲线特征相同,说明PUM100在试验剂量范围内与利妥昔单抗具有生物等效性。     

Pharmacokinetics of mebudipine, a new calcium antagonist, following single intravenous and oral administrations in rats

The pharmacokinetics of a new calcium antagonist, mebudipine, was studied after a single intravenous (0.5 mg/kg) and oral (10 mg/kg) administration to rats. After intravenous dosing, the plasma concentration of mebudipine declined biexponentially with a terminal half-life of 2.84 h. The blood clearance was 1.67 l/h/kg and the volume of distribution at steady state was found to be 6.26 l/kg. After oral dosing (10 mg/kg), the C(max) of mebudipine was 25.9+/-9.79 ng/ml. The oral bioavailability was low (< 2%) suggesting a marked first-pass effect. The distribution of mebudipine into some tissues such as brain, heart, liver and kidney following intravenous administration (0.5 mg/kg) was studied and a rapid distribution of mebudipine into these tissues was found. It was concluded that brain, heart, liver and kidney are in the same compartment as plasma (central).     

Pharmacokinetics of a novel surface-active agent,purified poloxamer 188, in rat,rabbit, dog and man

Purified poloxamer 188 (PP188) is a non-ionic, block copolymer surfactant that is currently being evaluated clinically in sickle cell disease vaso-occlusive crisis and acute chest syndrome and preclinically in spinal cord injury and muscular dystrophy. This paper describes the pharmacokinetics of PP188 in rats, pregnant rats, pregnant rabbits, dogs and humans. Plasma protein binding interaction studies demonstrated no clinically significant effects on narcotic analgesics, hydroxyurea, warfarin, diazepam or digitoxin, but an increase in free fraction for propranolol. The plasma concentrations increased proportionate with increasing dose in all species tested. Renal clearance accounted for 90% of total plasma clearance in man. A single metabolite was detected and quantified in the plasma from dogs and humans that was cleared more slowly than parent drug. Allometric scaling of plasma clearance and volume of distribution at steady-state (Vss) across species provided good predictions of the pharmacokinetic parameters in humans. Based on the comparative pharmacokinetics of PP188 in rat, rabbit, dog and man, all three animal species were appropriate models for evaluating various aspects of PP188's toxicological profile.     

Pharmacokinetics of α-dihydroergocriptine in rats after single intravenous and single and repeated oral administrations

The pharmacokinetics of α-dihydroergocriptine methane sulphonate in rats were investigated using an HPLC method for the detection of unchanged α-dihydroergocriptine (DHEK) in plasma, organs (kidneys, heart, lungs, spleen, liver, and brain), and urine. The plasma profile of DHEK obtained after intravenous administration at a dose of 5 mg kg^?1 (as base) of DHEK methane sulphonate showed a three compartment pharmacokinetic model with an elimination half-life of 6.78 h. The kinetics of DHEK after a single oral administration at a dose of 20 mg kg^?1 (as base) showed two peaks: the second peak, at about 6 h, was probably due to an enterohepatic cycle. The disposition of DHEK consisted of an absorption half-life of 0.02 h, a distribution half-life of 2.15 h and an elimination half-life of 5.83 h. The pharmacokinetics of DHEK, after repeated oral administrations at the same dose, were similar to those after a single oral administration. The absolute bioavailability was 4.14% after a single oral administration and 3.95% after repeated oral administrations. The analysis of the organs showed that DHEK was rapidly absorbed and distributed in all tissues, mostly in lungs, kidneys, and liver, but it is interesting to observe that it also reached the brain. After repeated oral administrations plasma and tissue concentrations were similar to those obtained after a single administration; therefore it is possible to exclude the onset of autoinduction or accumulation phenomena of DHEK in rats' organs. Urinary excretion of the unchanged drug was low (0.38% of the administered dose in the intravenous route and 0.04% in the oral route), being in agreement with a low oral bioavailability and a rapid and extensive metabolism (first-pass effect).     

Pharmacokinetic study of methylnaltrexone after single and multiple subcutaneous administrations in healthy Chinese subjects

1. Pharmacokinetics of methylnaltrexone (MNTX) were evaluated after subcutaneous administrations (s.c.) in healthy Chinese subjects.

2. In a cross-over single dose study, 12 subjects were given 0.075, 0.15, and 0.3?mg/kg of MNTX bromide injection. In a multiple doses study, another 12 subjects subcutaneously received 0.15?mg/kg of MNTX bromide injection every 48?h, in total five administrations. The concentrations of MNTX in plasma were quantified by LC–MS/MS.

3. After single s.c. administrations of 0.075, 0.15, and 0.3?mg/kg of MNTX bromide, C_max values of MNTX were 93.5?±?28.6, 191?±?37, and 364?±?54?ng/mL, respectively, and AUC_0–∞ were 88.8?±?8.8, 181?±?16, and 357?±?34?ng?h/mL, respectively. The t_1/2 of MNTX was about 7.7?h. After multiple doses administration, the C_max, C_av, AUC_ss, and MRT_0–∞ values were 191?±?50, 3.79?±?0.40?ng/mL, 182?±?19?ng?h/mL, and 3.56?±?1.17?h, respectively.

4. Methylnaltrexone bromide displayed dose-proportional pharmacokinetics in the dose range of 0.075–0.3?mg/kg. After multiple doses administration, t_1/2 was slightly prolonged, with the cumulative factor of 1.02. This study provides a pharmacokinetic reference after a single dose and multiple doses of MNTX bromide in Chinese subjects.     

Plasma profiles of lycopene after single oral and intravenous administrations in dogs

The objectives of this study were to identify the factors limiting the absorption of purified lycopene after oral administration, and to comparatively assess plasma data sets after single oral and intravenous administrations in dogs to define the conditions for performing an absolute bioavailability study. Solubility of purified lycopene (all-trans, 93.5%) was determined in media simulating the conditions in the fasted and in the fed upper gastrointestinal lumen. After evaluating the plasma levels achieved following single administrations of purified lycopene powder to fasted and fed dogs at escalating doses (75-750 mg), a crossover study was performed in four fed female mongrel dogs at two phases. In phase I, one soft gelatine capsule (10 mg lycopene) with 500 mL milk was administered orally. In phase II, 500 mL milk was administered orally and 250 mL 5% dextrose containing 5 mg lycopene in the form of a binary system with hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) was administered intravenously over 3.5 h. In-vitro and preliminary canine studies confirmed that, after oral administration of lycopene in solid form, arrival of lycopene into the systemic circulation was limited by lymphatic transport and, in addition, if the administered dose was higher than approximately 2 mg, by intralumenal solubility. During the first 50 h after single administrations to fed dogs, lycopene plasma levels were lower after intravenous than after oral administration. This could have been related to capacity limited elimination of lycopene and/or route-dependent disposition kinetics. Estimation of the amount of lycopene reaching the systemic circulation after oral and after intravenous administration requires separate estimations of total body clearance of lycopene.     

Carpipramine metabolism in the rat, rabbit and dog and in man after oral administration

Carpipramine administered orally is excreted via the urine and faeces in rat, rabbit, dog and man. Many metabolites are formed, including several conjugates in the urine. A total of 20-25 metabolites was detected by t.l.c. and h.p.l.c., 16 of which were isolated and identified. Three metabolic pathways were observed: hydroxylation of the iminodibenzyl ring to a phenol or alcohol without modification of the side-chain, hydroxylation of the terminal piperidine of the 2-piperidinol side-chain, and cyclization and dehydrogenation of the same 2-piperidinol group.     

Pharmacokinetic and pharmacodynamic studies following the intravenous and oral administration of the antiparkinsonian drug biperiden to normal subjects

Summary The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects.After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml·min^–1·kg^–1 and 24 l·kg^–1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism.Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.     

Pharmacokinetic study of a tripeptide HIV-1 protease inhibitor,KNI-174, in rats after intravenous and intraduodenal administrations

Recently, as a new type of anti-AIDS drug, an HIV-1 protease inhibitor, KNI-174, has been synthesized; it shows a potent and selective HIV-1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI-174 in rat plasma and examined the pharmacokinetics of KNI-174 in rats using this assay method after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailability of this new anti-AIDS drug. This HPLC assay method is specific to KNI-174 and the standard curve was linear from 0.02 to 30 μg ml^?1 plasma. After i.v. administration, 10.0 mg kg^?1, KNI-174 disappeared from the rats' plasma in a three-exponential decay. The mean terminal elimination half-life, t_1/2ÀZ, was 3.97 ± 0.19 (S.E.)h, the total body clearance, CL_tot, was 9.53 ± 1.08 ml min^?1 and the distribution volume at steady state, V_{d, ss}′ was 7070 ± 960 ml kg^?1. In the case of the i.d. administration, 10.0 mg kg^?1, the mean peak plasma concentration, C_max, and the peak time, t_max, were 0.196 ± 0.076 μg ml^?1 and 0.444 ± 0.193 h, respectively. The bioavailability of KNI-174 till infinity, BA^(0-infinity), was 5.37 per cent. Because the IC₅₀ of KNI-174 against HIV-1 in PHA-PBM was 138 ng ml^?1, the time needed for maintaining the concentrations above IC₅₀ after a single i.d. administration of KNI-174 is estimated to be 0.350 ± 0.184 h.     

Pharmacokinetics,metabolism, excretion and plasma protein binding of 14C-levofloxacin after a single oral administration in the Rhesus monkey

Levofloxacin's metabolism, excretion, and in vitro plasma protein binding, together with its pharmacokinetics, were studied in the Rhesus monkey in support of an anthrax efficacy study in this species. Three males and three female Rhesus monkeys were dosed with a single oral dose of ¹⁴C-levofloxacin at 15?mg?kg^?1 (2?MBq?kg^?1). Following dose administration, blood samples were collected up to 48?h post-dose, and urine and faeces were quantitatively collected up to 168?h post-dose. Blood, plasma, urine, and faeces were analysed for total radioactivity. Metabolite profiling and identification was performed using radio-high-performance liquid chromatography (HPLC) and liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS). Additionally, the plasma protein binding of levofloxacin was determined in vitro by means of equilibrium dialysis. Peak plasma levels of total radioactivity and levofloxacin were rapidly reached after oral administration with a total radioactivity blood: plasma ratio close to unity. The elimination half-life of levofloxacin was estimated at about 2?h. Total radioactivity was mainly excreted in urine (about 57–86% of the dose) with faecal excretion accounting for only a minor fraction of the total amount of excreted radioactivity (about 7.4–14.7%). In the plasma, the majority of total radioactivity was accounted for by levofloxacin. In addition, two minor metabolites, i.e. levofloxacin n-oxide and presumably a glucuronide conjugate of levofloxacin, were detected. In the urine, five components were found, with levofloxacin being the major component. Minor metabolites included desmethyl levofloxacin, levofloxacin n-oxide, and a glucuronide conjugate of levofloxacin. In the faeces, the major analyte was a polar metabolite, tentatively identified as a levofloxacin glucuronide. The in vitro plasma protein binding was low (on average 11.2%) and independent of concentration (1.0–10.0?µg?ml^?1). No sex differences were noted in any of the investigations. The present data indicated that the metabolism and excretion pattern, and also the in vitro plasma protein binding of levofloxacin in the Rhesus monkey, were comparable with those previously reported in man, hereby supporting the use of this animal species in the efficacy evaluation of levofloxacin against inhalation anthrax. The shorter half-life of levofloxacin in the Rhesus monkey relative to man (2 versus 7?h) prompted the development of an alternative dosing strategy for use in the efficacy study.     

大鼠一次性灌服酸枣仁提取物后棘苷的药代动力学研究

目的用反相高效液相色谱法,以磺胺甲唑为内标,对一次性ig酸枣仁提取物后的大鼠血浆中棘苷进行药代动力学研究。方法血浆样品经乙腈沉淀蛋白后,于50 ℃氮气流下吹干,残渣用流动相溶解后进行分析。色谱条件为色谱柱:Hypersil C₁₈柱,200 mm×4.6 mm ID,5 μm;流动相:乙腈-水-冰醋酸(15∶85∶1);流速:0.7 mL·min^-1;检测波长:334 nm;柱温:35 ℃。结果血浆中棘苷在18.1～903.5 μg·L^-1成良好线性关系(R²≥0.995)。平均回收率为94.5%,日内、日间精密度RSD均小于9.0%。该法定量限为18.1 μg·L^-1,血浆样品在-20 ℃可稳定保存。结论该法简便、灵敏、准确,可用于大鼠一次性灌服酸枣仁提取物后血浆中棘苷的浓度测定及其药代动力学研究。     

Species differences in blood profiles,metabolism and excretion of 14C-propofol after intravenous dosing to rat,dog and rabbit

1. Bolus i.v. doses of ¹⁴C-propofol (7–10?mg/kg) to rat, dog and rabbit, or an infusion dose (0.47mg/kg per?min for 6h) to dog were eliminated primarily in urine (60–95% dose); faecal elimination (13–31%) occurred for rat and dog, but was minimal (<2%) for rabbit.

2. After bolus administration, blood ¹⁴C concentrations were maximal (8–30 μg equiv./ml) at 2–15 min; these declined rapidly during the 0–2?h period and thereafter more slowly. Propofol concentrations were maximal (4–16 μ/ml) at 2?min and the profiles were best fitted by a tri-exponential (rat and dog) or bi-exponential (rabbit) equation. Duration of sleep ranged from 5 to 8?min.

3. Infusion of ¹C-propofol in dog gave a blood ¹⁴C concentration of 117 μg equiv./ml at the end of the 6?h infusion period; this declined at a similar rate to that after the bolus dose. Propofol concentration on termination of infusion was 13 μg/ml; thereafter, propofol concentrations declined less rapidly than after the bolus dose. Waking occurred about 44?min post-infusion.

4. Propofol was cleared by conjugation of the parent molecule or its quinol metabolite; hydroxylation of an isopropyl group also occurred in rat and rabbit. Biliary excretion leading to enterohepatic recirculation, and in turn increased sulphate conjugation, occurred in rat and dog, but not rabbit, resulting in a marked interspecies variation in drug clearance and metabolite profiles.     

Pharmacokinetics and metabolism of isosorbide-dinitrate after intravenous and oral administration

Summary The bioavailabilities of a conventional and two slow release 20 mg isosorbide dinitrate (ISDN) formulations were compared after oral administration in a three way cross-over study in 8 male volunteers. In a further group of 6 male volunteers the pharmacokinetics and metabolism of ISDN were investigated after intravenous infusion of a median dose of 14.1 mg for 2.5 h. A new analytical procedure was developed for the determination of isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-Glu) and of isosorbide (IS). Kinetic data analysis on a molar basis was performed by the program package KINPAK providing model independent parameters. The median elimination half-lives of ISDN, IS-5-MN, IS-2-MN and IS-5-MN-2-Glu were 0.7, 5.1, 3.2 and 2.5 h, respectively. The systemic clearance of ISDN was 3.7 l/min and the distribution volume 2521 (3.1 l/kg). Apart from IS-5-MN-2-Glu, with a renal clearance of 5.9 l/min which suggested substantial glucuronidation in the kidney, the renal clearances of ISDN, IS-5-MN, IS-2-MN and the corresponding amounts excreted were negligible. 27.8% of the administered ISDN was excreted as IS-5-MN-2-Glu (8.7%) and IS (19.1%). Calculations based on the two mononitrate metabolites formed from ISDN showed an incomplete recovery of 84.1%, leading to the assumption that a simultaneous denitration to IS must have occurred. The rate of denitration at each nitro group in ISDN was almost twice as high as for the same position in the corresponding mononitrate. The bioavailability of the conventional ISDN formulation was 19%, although complete absorption was indicated by comparison of the percentages of mononitrate metabolites formed after the different routes of administration. On the same basis the absorption of the two sustained release formulations was found to be poor.Preliminary results were presented at the 2nd World Conference on Clinical Pharmacology and Therapeutics, Washington, 1983     

Kinetics of allopurinol after single intravenous and oral doses

Summary An high-pressure liquid chromatographic method was used to measure allopurinol and oxipurinol in plasma and urine in 6 healthy volunteers after a single intravenous or oral dose of allopurinol. The influence of coadministrated benzbromarone and hydrochlorothiazide on the pharmacokinetics of allopurinol and oxipurinol was also investigated. After intravenous injection of allopurinol 300 mg the plasma disappearance was biexponential, with a mean distribution half-life of 2.32±1.08 min and an elimination half-life of 47.8±10.6 min. The total clearance of allopurinol was 11.37±2.70 ml/min/kg, whereas its renal clearance was only 1.73±0.79 ml/min/kg. Oxipurinol disappeared monoexponentially from plasma ith a mean half-life of 12.2±2.6 h. Its renal clearance was 0.42±0.091 ml/min/kg. After oral administration of allopurinol 300 mg the peak plasma concentration of 2.1±0.6 μg/ml (1.5×10⁻⁵ M) was reached within 30 to 120 min. The peak level of oxipurinol of 5.8±1.5 μg/ml (3.8×10⁻⁵ M) was found within 2 to 5 h after intravenous and oral allopurinol. The bioavailability of oral allopurinol computed from plasma data was 90.4±8.7%. The total recovery from urine was 77% (allopurinol 8%, oxipurinol 69%) after oral and 88% after i.v. administration. It was concluded that about 10% of the oral dose was not absorbed and that 12% was eliminated by an unknown mechanism, presumably as riboside. The pharmacokinetics of allopurinol and oxipurinol were not significantly influenced by coadministration of benzbromarone or hydrochlorothiazide. This work forms part of a thesis to be presented by M. Tittel to the Fachbereich Medizin der Justus Liebig-Universit?t Giessen     

Pharmacokinetics and metabolism of the antimalarial piperaquine after intravenous and oral single doses to the rat

This study aimed to evaluate the pharmacokinetic properties of piperaquine in the rat after intravenous and oral administration, and to identify and characterize the main piperaquine metabolites in rat plasma, urine, faeces and bile after intravenous administration. Male Sprague-Dawley rats were administered piperaquine as an emulsion orally or as a short-term intravenous infusion. Venous blood for pharmacokinetic evaluation was frequently withdrawn up to 90 h after dose. Urine, bile and faeces were collected after an infusion in rats kept in metabolic cages or in anesthetized rats. Pharmacokinetic characterization was done by compartmental modeling and non-compartmental analysis using WinNonlin. Piperaquine disposition was best described by a 3-compartment model with a rapid initial distribution phase after intravenous administration. The pharmacokinetics of piperaquine was characterized by a low clearance, a large volume of distribution and a long terminal half-life. Piperaquine displayed a low biliary clearance and less than 1% of the total dose was recovered in urine. The absolute oral bioavailability was approximately 50%. The main metabolite after intravenous administration of piperaquine was a carboxylic acid product identical to that reported in humans. The similarity with results in humans indicates the rat to be a suitable species for nonclinical in vivo piperaquine studies.     

Species differences in blood profiles, metabolism and excretion of 14C-propofol after intravenous dosing to rat, dog and rabbit.

1. Bolus i.v. doses of 14C-propofol (7-10 mg/kg) to rat, dog and rabbit, or an infusion dose (0.47 mg/kg per min for 6 h) to dog were eliminated primarily in urine (60-95% dose); faecal elimination (13-31%) occurred for rat and dog, but was minimal (less than 2%) for rabbit. 2. After bolus administration, blood 14C concentrations were maximal (8-30 micrograms equiv./ml) at 2-15 min; these declined rapidly during the 0-2 h period and thereafter more slowly. Propofol concentrations were maximal (4-16 micrograms/ml) at 2 min and the profiles were best fitted by a tri-exponential (rat and dog) or bi-exponential (rabbit) equation. Duration of sleep ranged from 5 to 8 min. 3. Infusion of 14C-propofol in dog gave a blood 14C concentration of 117 micrograms equiv./ml at the end of the 6 h infusion period; this declined at a similar rate to that after the bolus dose. Propofol concentration on termination of infusion was 13 micrograms/ml; thereafter, propofol concentrations declined less rapidly than after the bolus dose. Waking occurred about 44 min post-infusion. 4. Propofol was cleared by conjugation of the parent molecule or its quinol metabolite; hydroxylation of an isopropyl group also occurred in rat and rabbit. Biliary excretion leading to enterohepatic recirculation, and in turn increased sulphate conjugation, occurred in rat and dog, but not rabbit, resulting in a marked interspecies variation in drug clearance and metabolite profiles.     

Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing

The pharmacokinetics of a new serotonin 5-HT₂ antagonist, deramciclane, was studied. Single oral doses of 1, 3, 6 and 10 mg kg⁻¹ and intravenous doses of 1, 3 and 6 mg kg⁻¹ were administered in beagle dogs. Moreover, the steady state pharmacokinetics of 1, 3 and 6 mg kg⁻¹ doses were studied. Deramciclane was rapidly and completely absorbed from the gastrointestinal tract. Due to a moderate first-pass metabolism the absolute bioavailability was only 45–61%. Deramciclane had a large volume of distribution (32–37 L kg⁻¹) because of its lipophilic nature. Deramciclane was extensively metabolized after intravenous injection and only trace amounts of intact drug is excreted in the urine. The total body clearance decreased (from 32 to 17 L h⁻¹) as the dose increased. It is suggested that the metabolic capacity was not sufficient to eliminate deramciclane in a linear manner with increasing dose. Therefore, deramciclane exhibited nonlinear pharmacokinetics as the AUC_0–∞ increased disproportionally to the dose after both intravenous and oral dosing. Formation of the active metabolite, N-desmethyl deramciclane, was also nonlinear (p =0.0002). At steady state deramciclane accumulated less than 2-fold during repeated administration. Copyright © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetic and pharmacodynamic changes of furosemide after intravenous and oral administration to rats with alloxan-induced diabetes mellitus

Because some physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs to treat the disease, the pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.) and oral administration of the drug (6 mg per whole body weight) to control rats and alloxan-induced diabetes mellitus rats (AIDRs). After i.v. administration, the total body clearance (5.47 versus 7.05 mL min⁻¹ kg⁻¹) was significantly slower in AIDRs and this was due to significantly slower renal clearance (2.35 versus 4.33 mL min⁻¹ kg⁻¹) because the nonrenal clearance was comparable between two groups of rats. The 8 h urinary excretion of furosemide after i.v. administration decreased significantly (2280 versus 3760 μg) in AIDRs due to impaired kidney function; the glomerular filtration rate measured by creatinine clearance was significantly slower (2.86 versus 4.33 mL min⁻¹ kg⁻¹) and both the plasma urea nitrogen (43.5 versus 17.3 mg dL⁻¹) and kidney weight (0.953 versus 0.749% of body weight) increased significantly in AIDRs. This resulted in a significant decrease in the 8 h urine output per g kidney (17.8 versus 43.6 mL) in AIDRs. However, the 8 h diuretic efficiency was not significantly different between two groups of rats. After oral administration, the area under the plasma concentration–time curve from time 0 to 8 h decreased significantly in AIDRs (1200 versus 1910 μg·min mL⁻¹) due to considerably decreased absorption of furosemide from gastrointestinal tract of AIDRs. After oral administration, the 8 h urine output per g kidney (18.6 versus 36.4 mL) also decreased significantly in the AIDRs due to significantly decreased 8 h urinary excretion of furosemide (405 versus 2210 μg), however, the 8 h diuretic efficiency increased significantly (127 versus 35.2 mL mg⁻¹) in AIDRs. © 1998 John Wiley & Sons, Ltd.     

Disposition of quercetin in man after single oral and intravenous doses

Summary The pharmacokinetics of quercetin, a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8±1.2 min for the phase and 2.4±0.2 h for the phase (predominant half life), respectively. Protein binding was >98%. The apparent volume of distribution was small at 0.34±0.03 l/kg. Of the intravenous dose 7.4±1.2% was excreted in urine as a conjugated metabolite, and 0.65±0.1% was excreted unchanged. After oral administration no measurable plasma concentrations could be detected, nor was any quercetin found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in faeces after the oral dose was 53±5%, which suggests extensive degradation by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.Supported by grant Gu 86/3 from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, Germany (FRG).