Pharmacokinetic properties of albiflorin and paeoniflorin after oral administration of pure compound, Radix Paeoniae alba extract and danggui-shaoyao-san extract to rats

This study compared the pharmacokinetics of albiflorin (ALB) and paeoniflorin (PAE), respectively, after oral administration of ALB, PAE, Radix Paeoniae alba (RPA) extract, and Danggui-Shaoyao-San (DSS) extract to rats on separate occasions. Analytes were detected simultaneously with liquid chromatography-tandem mass spectrometry. Noncompartmental pharmacokinetic parameters were calculated. After oral administration of RPA and DSS extract to rats, ALB reached maximum concentrations of 4637?±?2774?ng/ml (0.40?±?0.14?h) and 226?±?122?ng/ml (0.35?±?0.14?h) and PAE reached maximum concentrations of 2132?±?560?ng/ml (0.40?±?0.14?h) and 143?±?65?ng/ml (0.45?±?0.11?h), respectively. Compared to the AUC(0?-?t) value (1122?±?351 and 722?±?158?ng?h/ml for ALB and PAE, respectively) after administration of monomers, larger AUC(0?-?t) value of ALB (4755?±?2560?ng?h/ml) and PAE (2259?±?910?ng?h/ml) after administration of RPA extract and smaller AUC(0?-?t) value of ALB (411?±?118?ng?h/ml) and PAE (242?±?126?ng?h/ml) after administration of DSS extract were obtained. The C(max), AUC, and K(el) of ALB and PAE were remarkably increased (P?相似文献   

Genotoxic effects of 4-methylimidazole on human peripheral lymphocytes in vitro

4-Methylimidazole (4-MEI), a heterocyclic organic chemical compound, is widely found in many foods and consumed by people worldwide. In this research, we aimed to investigate the cytotoxic and genotoxic effects of 4-MEI on human lymphocytes. For this purpose, human peripheral blood lymphocytes were treated with four concentrations of 4-MEI (300, 450, 600 and 750?μg/ml) for 24?h and 48?h periods and in vitro sister chromatid exchange (SCE), chromosome aberration (CA) and micronucleus (MN) tests were used. 4-MEI induced SCE in human peripheral lymphocytes at three highest concentrations (450, 600 and 750?μg/ml) in 48?h treatment period. CA and MN were induced in human peripheral lymphocytes at two highest concentrations of 4-MEI (600 and 750?μg/ml) in 24?h and 48?h treatment periods. The highest concentration of 4-MEI (750?μg/ml) induced MN formation more than the positive control MMC in 24?h treatment period. In addition, 4-MEI led to a decrease in MI at the highest concentration (750?μg/ml) in 24?h treatment period and at all concentrations in 48?h treatment period. 4-MEI reduced PI at all concentrations in 24?h treatment period and at all concentrations (expect the lowest) for 48?h treatment period. 4-MEI reduced nuclear division index (NDI) at 24 and 48?h treatment periods, even at the highest two concentrations, decreased more than the positive control MMC. Our results showed that 4-MEI pose a genotoxic and cytotoxic effects for human peripheral lymphocytes.     

Effect of genistein on the activities of cytochrome P450 3A and P-glycoprotein in Chinese healthy participants

To determine the effect of genistein on cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) function using the probe substrates midazolam and talinolol, respectively. Eighteen healthy adult male participants were enrolled in a two-phase randomized crossover design. In each phase, the participants received placebo or genistein for 14 days. On the 15th day, midazolam and talinolol were administered and blood samples were obtained. Midazolam and talinolol pharmacokinetic parameter values were calculated and compared before and after genistein administration. Co-administration of genistein decreased the area under the concentration-time curve from 0 to 36?h (AUC 0-36) (143.65?±?55.40?ng h/mL versus 126.10?±?40.14?ng h/mL, p?相似文献   

Adverse respiratory effects in rats following inhalation exposure to ammonia: respiratory dynamics and histopathology

Acute respiratory dynamics and histopathology of the lungs and trachea following inhaled exposure to ammonia were investigated. Respiratory dynamic parameters were collected from male Sprague–Dawley rats (300–350?g) during (20?min) and 24?h (10?min) after inhalation exposure for 20?min to 9000, 20,000, and 23,000?ppm of ammonia in a head-only exposure system. Body weight loss, analysis of blood cells, and lungs and trachea histopathology were assessed 1, 3, and 24?h following inhalation exposure to 20,000?ppm of ammonia. Prominent decreases in minute volume (MV) and tidal volume (TV) were observed during and 24?h post-exposure in all ammonia-exposed animals. Inspiratory time (IT) and expiratory time (ET) followed similar patterns and decreased significantly during the exposure and then increased at 24?h post-exposure in all ammonia-exposed animals in comparison to air-exposed controls. Peak inspiratory (PIF) and expiratory flow (PEF) significantly decreased during the exposure to all ammonia doses, while at 24?h post-exposure they remained significantly decreased following exposure to 20,000 and 23,000?ppm. Exposure to 20,000?ppm of ammonia resulted in body weight loss at 1 and 3?h post-exposure; weight loss was significant at 24?h compared to controls. Exposure to 20,000?ppm of ammonia for 20?min resulted in increases in the total blood cell counts of white blood cells, neutrophils, and platelets at 1, 3, and 24?h post-exposure. Histopathologic evaluation of the lungs and trachea tissue of animals exposed to 20,000?ppm of ammonia at 1, 3, and 24?h post-exposure revealed various morphological changes, including alveolar, bronchial, and tracheal edema, epithelial necrosis, and exudate consisting of fibrin, hemorrhage, and inflammatory cells. The various alterations in respiratory dynamics and damage to the respiratory system observed in this study further emphasize ammonia-induced respiratory toxicity and the relevance of efficacious medical countermeasure strategies.     

A pharmacokinetic, pharmacodynamic, and electrocardiographic study of liposomal mifamurtide (L-MTP-PE) in healthy adult volunteers

Purpose

This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [mifamurtide (L-MTP-PE)] in healthy adults.

Methods

L-MTP-PE 4?mg was administered intravenously over 30?min. Study participants were monitored from 24?h preinfusion until 72?h postinfusion. Blood samples were drawn over 0–72?h postdose to determine serum MTP-PE, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) concentrations. Electrocardiograpic (ECG) data were collected via continuous Holter monitoring beginning 24?h predose through 24?h postdose. Changes from time-matched pretreatment baseline QTc and associated two-sided 90?% confidence intervals were calculated.

Results

Twenty-one participants received L-MTP-PE. Total serum MTP-PE declined rapidly with a terminal half-life of 2.05?±?0.40?h. PK variability was low, with <30?% coefficient of variation in systemic exposure. Serum concentrations of IL-6, TNF-α, and CRP increased following L-MTP-PE infusion. Maximum observed increases in IL-6 and TNF-α occurred at 4 and 2?h, respectively, returning toward baseline by 8?h postdose. L-MTP-PE was generally well tolerated, with no adverse events greater than grade 3. Headache, chills, tachycardia, nausea, and pyrexia were the most frequent adverse events. L-MTP-PE infusion resulted in an increased heart rate without readily apparent QTc prolongation.

Conclusions

MTP-PE PK following L-MTP-PE administration were characterized by a short serum half-life and low variability. Increases in IL-6, TNF-α, and CRP and the safety profile were consistent with the immunomodulatory mechanism of action. No clinically significant effect of L-MTP-PE on cardiovascular repolarization was observed based on analysis of ECG QTc intervals.     

Influence of Molecular Size on the Retention of Polymeric Nanocarrier Diagnostic Agents in Breast Ducts

Purpose

To investigate the influence of nanocarrier molecular size and shape on breast duct retention in normal rats using a non-invasive optical imaging method.

Methods

Fluorescein-labeled PEG nanocarriers of different molecular weights and shapes (linear, two-arm, four-arm, and eight-arm) were intraductally administered (50?nmol) to female Sprague?CDawley rats. Whole body images were obtained non-invasively. Fluorescence intensities (i.e., amount remaining in duct) were plotted against time to estimate the nanocarrier ductal retention half-lives (t_1/2). Plasma samples were taken and the pharmacokinetics (Tmax, Cmax) of absorbed nanocarriers was also assessed.

Results

The t_1/2 of linear 12, 20, 30, 40, and two-arm 60?kDa nanocarriers were 6.7?±?0.9, 16.1?±?4.1, 16.6?±?3.4, 21.5?±?2.7, and 19.5?±?6.1?h, whereas the four-arm 20, 40, and eight-arm 20?kDa had t_1/2 of 9.0?±?0.5, 11.5?±?1.9, and 12.6?±?3.0?h. The t_1/2 of unconjugated fluorescein was significantly lower (14.5?±?1.4?min). The Tmax for 12, 40, 60?kDa nanocarriers were 1, 24, and 32?h, respectively, and only 30?min for fluorescein.

Conclusions

Since normal breast ducts are highly permeable, the use of nanocarriers may be helpful in prolonging ductal retention of diagnostic and/or therapeutic agents.     

Comparison of the physiological and morphological effects of cigarette smoke exposure at comparable weekly doses on Sprague-Dawley rats

A variety of dose x duration exposure regimens have been used in inhalation toxicity studies using rodents. We evaluated the effects of differences in smoke concentration and daily exposure duration under similar weekly cumulative exposures in rats to determine potential variation in type and severity of adverse effects in 13-week exposure studies. The weekly cumulative dosages were 2100 and 4200?μg wet total particle matter (WTPM)/L, and the daily exposure durations were 1 and 6?h. Weekly exposure duration was 5 or 7 days/week for groups exposed 1?h/day and 7 days/week for groups exposed 6?h/day. Recovery duration was 6 and 13 weeks. Mainstream smoke exposure suppressed body weight (BW) gain in both regimens. Lower dose groups exposed 1?h/day had a consistently greater of BW gain compared with corresponding 6?h/day groups. Respiratory rate, tidal volume, and minute volume (MV) were suppressed in a dose-dependent manner in both regimens. Higher MV in rats exposed for 6?h/day compared with rats exposed 1?h/day suggested that a lower concentration for longer duration resulted in a greater total inhaled mass (TIM) in rats exposed 6?h/day. Groups exposed for 6?h/day had lower blood carboxyhemoglobin and plasma nicotine levels than groups exposed 1?h/day, reflecting the lower carbon monoxide (CO) and WTPM concentrations in the 6?h/day groups. Data from examination of bronchoalveolar lavage fluids (BALF) and respiratory tract tissues indicated comparable effects between both regimens. Exposure-induced histopathological changes regressed similarly for both regimens after the recovery periods.     

Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension

Purpose

Clevidipine is a rapidly-acting intravenous dihydropyridine antihypertensive acting via calcium channel blockade. This was a randomized, single-blind, parallel-design study of a 72-h continuous clevidipine infusion.

Method

Doses of 2, 4, 8, or 16.0?mg/h or placebo were evaluated in 61 subjects with mild to moderate essential hypertension. IV clevidipine or placebo was initiated at 2.0?mg/h and force-titrated in doubling increments every 3?min to target dose, then maintained for 72?h. Blood pressure and heart rate were measured during infusion, and for 4, 6 and 8?h after termination of infusion, although oral therapy could be restarted at 4?h. Clevidipine blood levels were obtained during infusion and for 1?hour after termination.

Results

Rapid onset of drug effect occurred at all clevidipine dose levels, with consistent pharmacokinetics and rapid offset after 72-h infusion. No evidence of tolerance to the clevidipine drug effect was observed at any dose level over the 72-h infusion. No evidence of rebound hypertension was found for either 4 or 6?h after termination of the clevidipine infusion. At 8?h following cessation of clevidipine, blood pressure was not significantly higher than at baseline. Placebo-treated subjects had blood pressures lower than baseline at 8?h following infusion termination; hence, placebo-adjusted blood pressures tended to be slightly higher than baseline.

Conclusion

This study supports the use of up to 72?h of IV clevidipine therapy for the management of blood pressure, with consistent pharmacokinetic/pharmacodynamic characteristics and context insensitive half-life across the dose ranges evaluated.     

Absorption of different oral dosage forms of oxycodone in the elderly: a cross-over clinical trial in patients undergoing cystoscopy

Purpose

To characterize the pharmacokinetics (PK) of oxycodone following intravenous injection and administration of three oral dosage forms (solution, capsule, and controlled-release tablet) in elderly patients (age 76–89?years) undergoing cystoscopy.

Methods

This was an open, randomized study with two sequences and two visits in 15 elderly patients. The patients were given intravenous injection (over 10?min) of 5?mg of oxycodone hydrochloride trihydrate. Oxycodone hydrochloride (5?mg in all forms) was orally administered as a solution, a capsule, and a controlled-release tablet. Venous blood samples were collected up to 17?h after oxycodone administration. Population PK parameters were calculated with NONMEM VI 2.0. For intravenous injection we calculated clearance, volume of distribution at steady state, and the half-life of elimination, and for oral dosage forms also the absolute bioavailability.

Results

Clearance of the intravenous injections was 28.9?L/h; the volume of distribution at steady state and the half-life of elimination were 186?L and 5.2?h, respectively. The absolute bioavailability of oxycodone was 59?% from oral solutions, 64?% from capsules, and 55?% from controlled-release tablets.

Conclusions

Our results indicate that, in the elderly, the bioavailability of the three different oral dosage forms of oxycodone is fairly similar.     

Fluorescence Imaging of the Lymph Node Uptake of Proteins in Mice after Subcutaneous Injection: Molecular Weight Dependence

Purpose

To use noninvasive fluorescence imaging to investigate the influence of molecular weight (MW) of proteins on the rate of loss from a subcutaneous (SC) injection site and subsequent uptake by the draining lymph nodes in mice.

Methods

Bevacizumab (149?kDa), bovine serum albumin (BSA, 66?kDa), ovalbumin (44.3?kDa) or VEGF-C156S (23?kDa), labeled with the near infrared dye IRDye 680, were injected SC into the front footpad of SKH-1 mice. Whole body non-invasive fluorescence imaging was performed to quantitate the fluorescence signal at the injection site and in axillary lymph nodes.

Results

The half-life values, describing the times for 50% loss of proteins from the injection site, were 6.81?h for bevacizumab, 2.85?h for BSA, 1.57?h for ovalbumin and 0.31?h for VEGF-C156S. The corresponding axillary lymph node exposure, represented as the area of the % dose versus time curve, was 6.27, 5.13, 4.06 and 1.54% dose ? h, respectively.

Conclusions

Our results indicate that the rate of loss of proteins from a SC injection site is inversely related to MW of proteins, while lymph node exposure is proportionally related to the MW of proteins in a mouse model.     

Uptake and Biotransformation of 6,7-Dimethylquinoline and 6,8-Dimethylquinoline by Rainbow Trout (Salmo Gairdneri)

1. 6,7-Dimethylquinoline (6,7-DMQ) is readily taken up by rainbow trout and bioconcentrated in tissue after exposure to ca 1?mg/1 for 7.5?h. Mean bioconcentration factors (from water) were 21, 18, 6 and 14 for bile, liver, muscle and carcass respectively. Mean tissue concentrations after 69-96?h depuration were ND, ND, 0.54 and 0.48 μg/g for bile, liver, muscle and carcass respectively.

2. Major metabolites, following exposure to 6,7-DMQ, were conjugates (glucuronide or sulphate) of 7-hydroxymethyl-6-methylquinoline and 6-hydroxymethyl-7-methylquinoline. Mean concentration of metabolites in the bile were 500μg/g after 7.5?h exposure to ca 1?mg/1 and 1367 μg/g after 9.5?h exposure to ca 1?mg/1 and 69?h depuration.

3. 6,8-Dimethylquinoline (6,8-DMQ) is also readily bioconcentrated in fish tissue after exposure to ca 1?mg/1. Mean bioconcentration factors (from water) were 23, 20, 13 and 25 for bile, liver, muscle and carcass respectively. Mean tissue concentrations after 7?h exposure to ca 1?mg/1 and 63?h depuration were 4.0,0.67,0.49, and 3.2 μg/g respectively for bile, liver, muscle and carcass.

4. Major metabolites, following exposure to 6,8-DMQ were conjugates (glucuronide or sulphate) of 6,8-dimethyl-5-hydroxyquinoline, 6,8-dimethyl-7-hydroxyquinoline. 6,8-dimethyl-3-hydroxyquinoline and 6-hydroxymethyl-8-methylquinoline. Mean concentration of metabolites in the bile were 1278 μg/g after exposure to ca 1?mg/1 for 8?h and 1031 μg after exposure to ca 1?mg/1 for 7h and 63?h depuration.     

Effect of yohimbine stress on reacquisition of oxycodone seeking in rats

Rationale

Stress, a powerful precipitant of drug seeking during abstinence, may also accelerate the return to pathological patterns of intake after initial instances of drug reuse.

Objective

To explore the effect of stress on a learning process underlying relapse, this study assessed the effect of yohimbine on reacquisition of oxycodone seeking.

Methods

One hundred thirty-two male Sprague?CDawley rats underwent place conditioning with oxycodone (2?mg/kg, SC; ×6?days), extinction (vehicle?×?6?days), and reconditioning with 0, 0.25, 2, or 5?mg/kg oxycodone (2?days). Yohimbine (0, 2.5, or 5?mg/kg, IP) was administered 30?min prior to reconditioning.

Results

Pretreatment with 2.5?mg/kg yohimbine increased, while 5?mg/kg yohimbine decreased, reacquisition of oxycodone-induced place preference. A follow-up study (n?=?30) further indicated that the effect of yohimbine was specific to reacquisition.

Conclusion

The observation that yohimbine can enhance reacquisition of oxycodone seeking supports the hypothesis that stress can facilitate learning processes involved in the unfolding of relapse.     

Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses

An individual (male, 36?years, 87?kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60?μg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48?h post-dose. For both DnBP and DiBP, the majority of the dose was excreted in the first 24?h (92.2?% of DnBP, 90.3?% of DiBP), while only <1?% of the dose was excreted in urine on day 2. In each case, the simple monoesters were the major metabolites (MnBP, 84?%; MiBP, 71?%). For DnBP, ~8?% was excreted as various side chain oxidized metabolites. For DiBP, approximately 20?% was excreted mainly as the oxidized side chain metabolite 2OH-MiBP, indicating that the extent of oxidative modification is around 2.5 times higher for DiBP than for DnBP. All DnBP and DiBP metabolites reached peak concentrations between 2 and 4?h post-exposure, followed by a monotonic decline. For DnBP metabolites, the elimination halftime of MnBP was 2.6?h; longer elimination halftimes were estimated for the oxidized metabolites (2.9–6.9?h). For DiBP metabolites, MiBP had the shortest halftime (3.9?h), and the oxidized metabolites had somewhat longer halftimes (4.1 and 4.2?h). Together with the simple monoesters, secondary oxidized metabolites are additional and valuable biomarkers of phthalate exposure. This study provides basic human metabolism and toxicokinetic data for two phthalates that have to be considered human reproductive toxicants and that have been shown to be omnipresent in humans.     

Measurement of various respiratory dynamics parameters following acute inhalational exposure to soman vapor in conscious rats

Abstract

Respiratory dynamics were investigated in head-out plethysmography chambers following inhalational exposure to soman in untreated, non-anesthetized rats. A multipass saturator cell was used to generate 520, 560 and 600?mg?×?min/m³ of soman vapor in a customized inhalational exposure system. Various respiratory dynamic parameters were collected from male Sprague-Dawley rats (300--350?g) during (20?min) and 24?h (10?min) after inhalational exposure. Signs of CWNA-induced cholinergic crisis were observed in all soman-exposed animals. Percentage body weight loss and lung edema were observed in all soman-exposed animals, with significant increases in both at 24?h following exposure to 600?mg?×?min/m³. Exposure to soman resulted in increases in respiratory frequency (RF) in animals exposed to 560 and 600?mg?×?min/m³ with significant increases following exposure to 560?mg?×?min/m³ at 24?h. No significant alterations in inspiratory time (IT) or expiratory time (ET) were observed in soman-exposed animals 24?h post-exposure. Prominent increases in tidal volume (TV) and minute volume (MV) were observed at 24?h post-exposure in animals exposed to 600?mg?×?min/m³. Peak inspiratory (PIF) and expiratory flow (PEF) followed similar patterns and increased 24?h post-exposure to 600?mg?×?min/m³ of soman. Results demonstrate that inhalational exposure to 600?mg?×?min/m³ soman produces notable alterations in various respiratory dynamic parameters at 24?h. The following multitude of physiological changes in respiratory dynamics highlights the need to develop countermeasures that protect against respiratory toxicity and lung injury.     

Lead accumulation pattern and molecular biomarkers of oxidative stress in seabream (Sparus aurata) under short-term metal treatment

The present work aimed to look at the distribution and accumulation pattern of Lead (Pb) within the fish body after 2?h, 4?h and 24?h of waterborne exposure to the metal at 0.75?mg/L. Tests of lead acute toxicity and bioaccumulation were performed in the common fish species Sparus aurata. In our study, we assessed the oxidative stress damages extent after 2?h, 4?h and 24?h of exposure to lead using the enzymatic stress biomarkers: Superoxide Dismutase (SOD), Catalase (CAT) and Gluthathione (GSH). The lipid peroxidation (LPO) was also investigated by dosing Malondyhaldéhyde (MDA) quantities in the liver tissue. The acute neurotoxicity of Pb was evaluated in the dorsal white muscle using the Acethylcholenesterase (AchE) activity. The liver tissue accumulates preferentially the metal, followed by the intestines, the gills and finally the dorsal muscle. The antioxidant response failed to prevent the lipid peroxidation and the neurotoxic effect of lead after 24?h of exposure.     

Comparative metabolism of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and dog

1. There is a significant species difference in the toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D). The oral no overall adverse effect level (NOAEL) for chronic toxicity of 2,4-D in rat is 5?mg kg ? 1 day ? 1 and in dog is 1?mg kg ? 1 day ? 1. The maximum tolerated dose (MTD) in rat is 150 and 75 kg ? 1 day ? 1 for male and females, respectively. The MTD in dog is 7.5?mg kg ? 1 day ? 1 for males and females. 2. In an attempt to explain the increased sensitivity to 2,4-D in dog, male and female rats and dogs were orally dosed with either 5 or 50?mg kg ? 1 14 C-2,4-D. The rates and routes of excretion were investigated along with plasma toxicokinetics and biotransformation of the compound. 3. Elimination of the radioactive dose of 2,4-D from rat plasma was significantly faster than in dog. The approximate t ½ were 1.3-3.4?h for rat and 99-134?h for dog following a 5 or 50?mg kg ? 1 dose, respectively. This led to large differences in the calculated AUC (0- ∝) 21-57 μ eq.?h?g ? 1 for rat and 4889-5298 µg eq.?h?g ? 1 for dog at 5?mg kg ? 1, and 122-2358 µg eq.?h?g ? 1 for rat and 34 110-44 296 µg eq.?h?g ? 1 for dog at 50?mg kg ? 1). 4. In rat, the major route of excretion was in the urine. Excretion was essentially complete after 24?h for the low dose and after 48?h for the high dose. For dog, elimination was incomplete over the sampling period with only about 50% of the dose recovered. Urine was the principal route of excretion at the low dose, but about equal amounts were excreted in urine and faeces at the high dose over 120?h. 5. In rat, 2,4-D was unmetabolized and excreted in urine as the parent compound. In dog, the dose was excreted mainly following metabolism. 2,4-D in dog was conjugated forming the taurine, serine, glycine, glutamic acid, cysteine, sulphate and glucuronide conjugates, plus an unidentified metabolite, which were excreted in urine. Plasma, however, only contained unmetabolized 2,4-D. 6. The results show that the body burden of 2,4-D in dog is significantly higher than in rat for an equivalent dose, which is consistent with the increased sensitivity of dog to 2,4-D toxicity.     

Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase

Purpose

We investigated the population pharmacokinetics and exposure-response relationship of nilotinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase.

Methods

Nilotinib was given at 300?mg or 400?mg twice daily. Serum concentration data (sparse and full pharmacokinetic profiles) were obtained from 542 patients over 12?months. A population pharmacokinetic analysis was performed using nonlinear mixed-effect modeling. Exposure-response relationships were explored graphically or using logistic regression models.

Results

Nilotinib concentrations were stable over 12?months. Patients in the 400?mg twice-daily arm had an 11.5% higher exposure than did those in the 300?mg twice-daily arm, and the relative bioavailability of nilotinib 400?mg twice daily was 0.84 times that of 300?mg twice daily. Patient demographics did not significantly affect nilotinib pharmacokinetics. The occurrence of all-grade total bilirubin elevation was significantly higher in patients with higher nilotinib exposure, and a positive correlation was also observed between nilotinib exposure and QTcF change on electrocardiograms from baseline. There was no significant relationship between nilotinib exposure and major molecular response at 12?months.

Conclusions

There is a less than proportional dose-exposure relationship between nilotinib 300?mg and 400?mg twice-daily doses. Blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed CML treated with nilotinib.     

Hepatotoxicity of ketoconazole in Sprague-Dawley rats: glutathione depletion,flavin-containing monooxygenases-mediated bioactivation and hepatic covalent binding

1. This study has examined ketoconazole (KT)-induced hepatotoxicity in vivo and in vitro, using male Sprague-Dawley rats with [3 H]KT (1.5 µCi?mg ? 1) at 40 and 90?mg KT kg ? 1 doses. Blood and liver samples were collected from 0 to 24?h for alanine aminotransaminase (ALT), glutathione (GSH) and covalent binding analyses. 2. Covalent binding occurred as early as 0.5?h, peaked at 2?h (0.026 ± 0.01 nmol KT?mg ? 1 protein) and 8?h (0.088 ± 0.04 nmol KT?mg ? 1 protein) for 40 and 90?mg KT kg ? 1 doses, respectively. ALT levels increased at 0.5?h for the 40 and 90?mg KT kg ? 1 doses (44.3 and 56.4 U ml ? 1, respectively) relative to control, 22.7 U ml ? 1. At 24?h, the 90?mg KT kg ? 1 dose reduced hepatic GSH levels from 9.92 ± 1.1 to 4.76 ± 0.3 nmol GSH?mg ? 1 protein. 3. The role of the flavin-containing monooxygenases (FMO) utilized Sprague-Dawley microsomes with 1, 10 and 100 µM [3 H]KT. Maximum covalent binding occurring at 100 µM KT. Heat inactivation of microsomal FMO significantly decreased covalent binding by 75%, whereas 1 mM GSH significantly reduced covalent binding by 65%. 4. Thus, KT-induced hepatotoxicity is dose- and time-dependent and appears to be FMO mediated, in part, to metabolites that may react with protein and, possibly, GSH.