A PHARMACOKINETIC STUDY WITH THE HIGH-DOSE ANTICANCER AGENT MENADIONE IN RABBITS

The aim of this investigation was to assess the pharmacokinetic properties of high-dose menadione (VK₃), as an anticancer agent, in plasma and red blood cells (RBCs) in rabbits. An extremely high dose of 75 mg menadiol sodium diphosphate (Synkayvite) was intravenously injected. HPLC analysis was applied to measure the major metabolite, menadione, VK₃. The kinetic properties of VK₃ in both plasma and red blood cells showed a short elimination half-life, high clearance, and large volume of distribution in plasma and RBCs. The mean elimination t_1/2 values of menadione in plasma and in RBCs were 27·17±10·49 min and 35·22±11·82 min, respectively. The plasma clearance (CL/F) of VK₃ was 0·822±0·254 L min⁻¹. The systemic clearance in RBCs was 0·407±0·152 L min⁻¹. The apparent volume of distribution (V_d/F) in plasma was 30·833±12·835 L and that in RBCs 20·488±9·401 L. The plasma AUC was 32·453±9·785 μg min mL⁻¹ and that of RBCs 67·219±24·449 μg min mL⁻¹. Menadiol was rapidly biotransformed to menadione in blood. The formation rate constant (k_f) of menadione in plasma was 0·589±0·246 min⁻¹, and that of RBCs 1·520±1·345 min⁻¹. Through this study the estimated menadione dosage needed to maintain a plasma level of 1 μg mL⁻¹ for anticancer purposes was 19·7 mg kg⁻¹ every hour.     

Pharmacokinetics and tissue disposition of danofloxacin in sheep

The plasma pharmacokinetics of danofloxacin administered at 1.25 mg kg⁻¹ body weight by the intravenous and intramuscular routes were determined in sheep. Tissue distribution was also determined following administration by the intramuscular route at 1.25 mg kg⁻¹ body weight. Danofloxacin had a large volume of distribution at steady state (V_ss) of 2.76±0.16 h (mean±S.E.M.) L kg⁻¹, an elimination half-life (t_1/2β) of 3.35±0.23 h, and a body clearance (C1) of 0.63±0.04 L kg⁻¹ h⁻¹. Following intramuscular administration it achieved a maximum concentration (C_max) of 0.32±0.02 μg mL⁻¹ at 1.23±0.34 h (t_max) and had a mean residence time (MRT) of 5.45±0.19 h. Danofloxacin had an absolute bioavailability (F) of 95.71±4.41% and a mean absorption time (MAT) of 0.81±0.20 h following intramuscular administration. Mean plasma concentrations of >0.06 μg mL⁻¹ were maintained for more than 8 h following intravenous and intramuscular administration. Following intramuscular administration highest concentrations were measured in plasma (0.43±0.04 μg mL⁻¹), lung (1.51±0.18 μg g⁻¹), and interdigital skin (0.64±0.18 μg g⁻¹) at 1 h, duodenal contents (0.81±0.40 μg mL⁻¹), lymph nodes (4.61±0.35 μg g⁻¹), and brain (0.06±0.00 μg mL⁻¹) at 2 h, jejunal (10.50±4.31 μg mL⁻¹) and ileal (5.25±1.67 μg mL⁻¹) contents at 4 h, and colonic contents (8.94±0.65 μg mL⁻¹) at 8 h. © 1998 John Wiley & Sons, Ltd.     

THE EFFECT OF CHANGES IN GASTRIC pH INDUCED BY OMEPRAZOLE ON THE ABSORPTION AND RESPIRATORY DEPRESSION OF METHADONE

The effect of omeprazole (2 mg kg⁻¹ i.v.) on respiratory depression induced in rats by acute oral methadone administration (5 mg kg⁻¹) was examined and compared with control animals that only received methadone. Quantitative assessments of arterial p_CO2, p_O2, pH, and respiratory rate were employed as criteria for evaluation. Intragastric pH was measured in each rat immediately before and 2 h after methadone. Plasma concentration of methadone was measured for 3 h. The relationship between drug effect and the systemic bioavailability of methadone, measured as the area under the plasma concentration–time curve (AUC_0–180 ), was also evaluated. The intensity of the methadone-induced respiratory depression was significantly greater in the omeprazole group than in control rats. A significant variation (p<0·01) in all respiratory parameters was detected from 30 to 120 min after methadone. Omeprazole caused a significant increase in methadone levels (C_max=156± 6·5 ng mL⁻¹ against 51±5·8 ng mL⁻¹ in control; p<0·05). AUC_0–180 was higher (p<0·05) after omeprazole treatment (18·6±1·4 μg mL⁻¹ min) than in control (6·8± 0·6 μg mL⁻¹ min). Two hours after treatment with omeprazole, intragastric pH values were significantly elevated (4·7±0·1 against 2·2±0·04) and continued increasing, being 6·4±0·1 at the end of the experiment. Correlation was observed between intragastric pH and the area under the effect– (respiratory depression–) time curve (r=0·74; p<0·001). A relationship between plasma methadone levels at 120 min and gastric pH (r=0·92; p<0·001) was detected. A significant correlation between the area under the effect–time curve (0–120 min) and AUC_0–180 has been also observed (r=0·90; p<0·01). These pharmacokinetic and pharmacodynamic changes could be gastric pH dependent because they were mimicked when gastric pH was experimentally modified by bicarbonate whereas opposite results were obtained with acidic pH 2 solution.     

Determination of higenamine in multi-matrix by gas chromatography-mass spectrometry combined with derivatization technology

Higenamine (HG), a cardioactive component of some foods and medicines, has been listed in the doping category by the International Olympic Committee, which may lead to misuse by athletes. We report the development of a gas chromatography-mass spectrometry (GC–MS) method for determination of HG in various matrix samples (biological samples, different forms of Chinese patent medicine, Chinese herbal medicine) based on acylation derivatization of HG by heptafluorobutyric anhydride. Under optimal conditions, the linearity of HG in the range of 5–200 ng mL⁻¹ was acceptable (R² > 0.999), and the limit of detection (LOD) and limit of quantitation (LOQ) for HG was 1.52 ng mL⁻¹ and 5 ng mL⁻¹, respectively. Low, medium, and high concentrations (25, 100 and 160 ng mL⁻¹) of HG were added to plasma, urine, oral liquid, capsule, watered bolus, honeyed bolus and Chinese herbal medicine samples, with recovery ranging from 82.70 to 109.80%, intra-day and inter-day precisions were both less than 3.39%. The results indicated that the method had sufficient sensitivity for analysis of biological samples, and Chinese patent and herbal medicine.     

Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination

Diltiazem and hydrochlorothiazide are widely used to treat cardiovascular disease, often in combination. The purpose of this investigation was to determine whether a drug–drug pharmacokinetic interaction exists between diltiazem and hydrochlorothiazide. In a randomized, crossover, open study, multiple doses of diltiazem (60 mg four times daily for 21 doses) and hydrochlorothiazide (25 mg twice daily for 11 doses) were administered alone and in combination on three separate occasions to 20 healthy male volunteers. Trough and serial blood samples were collected and plasma was assayed for diltiazem, hydrochlorothiazide, and diltiazem metabolites (desacetyldiltiazem and N-desmethyldiltiazem) using HPLC. Total urine was also collected and quantified for hydrochlorothiazide. Coadministered hydrochlorothiazide did not significantly (p >0.05) alter diltiazem (alone versus combination) steady-state maximum plasma concentration (C; 145 versus 158 ng mL⁻¹, respectively), time to maximum plasma concentration (t_max; 3.0 versus 2.8 h, respectively); area under the plasma concentration–time curve (AUC_ss; 688 versus 771 ng·h mL⁻¹), oral clearance (Cl_oral; 96.2 versus 88.0 L h⁻¹), or elimination half-life (t_1/2; 5.2 versus 5.2 h). Similarly, administration of diltiazem did not significantly (p >0.05) influence hydrochlorothiazide (alone versus combination) C (221 versus 288 ng mL⁻¹), t_max (1.8 versus 2.0 h), AUC_ss (1194 versus 1247 ng·h mL⁻¹), Cl_oral (22.4 versus 21.2 L h⁻¹); t_1/2 (9.8 versus 9.6 h), or renal Cl (15.5 versus 15.2 L h⁻¹). In conclusion, a clinically significant pharmacokinetic interaction between diltiazem and hydrochlorothiazide does not exist. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition

DMXBA (3-(2, 4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg⁻¹ iv dose, DMXBA plasma concentration declined bi-exponentially with mean (±SE) absorption and elimination half-lives of 0.71±0.28 and 3.71±1.12 h, respectively. The apparent steady state volume of distribution was 2150±433 mL kg⁻¹, total body clearance was 1480±273 mL h⁻¹ kg⁻¹, and AUC_0–∞ was 3790±630 ng h mL⁻¹. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg⁻¹, a peak plasma concentration of 1010±212 ng mL⁻¹ was observed at 10 min after dosing. Elimination half-life was 1.740±0.34 h, and AUC_0–∞ was 1440±358 ng h mL⁻¹. DMXBA peak brain concentration after oral administration was 664±103 ng g⁻¹ tissue, with an essentially constant brain–plasma concentration ratio of 2.61±0.34, which indicates that the drug readily passes across the blood–brain barrier. Serum protein binding was 80.3±1.1%. Apparent oral bioavailability was 19%. Renal clearance (21.8 mL h⁻¹ kg⁻¹) was less than 2% of the total clearance (1480±273 mL h⁻¹ kg⁻¹); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28±0.03% of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism. © 1998 John Wiley & Sons, Ltd.     

International patent applications for non‐injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database

Issues. Non‐injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer‐reviewed domain. Through examination of a hitherto‐unsearched database, we expand public knowledge of non‐injectable formulations, tracing their development and novelty, with the aim to describe and compare their pharmacokinetic properties. Approach. (i) The PatentScope database of the World Intellectual Property Organization was searched for relevant English‐language patent applications; (ii) Pharmacokinetic data were extracted, collated and analysed; (iii) PubMed was searched using Boolean search query ‘(nasal OR intranasal OR nose OR buccal OR sublingual) AND naloxone AND pharmacokinetics’. Key Findings. Five hundred and twenty‐two PatentScope and 56 PubMed records were identified: three published international patent applications and five peer‐reviewed papers were eligible. Pharmacokinetic data were available for intranasal, sublingual, and reference routes. Highly concentrated formulations (10–40 mg mL⁻¹) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non‐concentrated intranasal spray (1 mg mL⁻¹; 1 mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (≥10 mg mL⁻¹) had bioavailability of 21–42% (relative to intravenous) and 26–57% (relative to intramuscular), with peak concentrations (dose‐adjusted C_max = 0.8–1.7 ng mL⁻¹) reached in 19–30 min (t_max). Implications. Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume. Conclusion. We find consistent direction of development of intranasal sprays to high‐concentration, low‐volume formulations with bioavailability in the 20–60% range. These have potential to deliver a therapeutic dose in 0.1 mL volume. [McDonald R, Danielsson Glende Ø, Dale O, Strang J. International patent applications for non‐injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev 2017;00:000‐000]     

Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting

The estradiol(E₂)-loaded chitosan nanoparticles (CS-NPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP). The CS-NPs had a mean size of (269.3 ± 31.6) nm, a zeta potential of +25.4 mV, and loading capacity of E₂ CS-NPs suspension was 1.9 mg ml⁻¹, entrapment efficiency was 64.7% on average. Subsequently, this paper investigated the levels of E₂ in blood and the cerebrospinal fluid (CSF) in rats following intranasal administration of E₂ CS-NPs. E₂-loaded CS-NPs were administered to male Wister rats either intranasally or intravenously at the dose of 0.48 mg kg⁻¹. The plasma levels achieved following intranasal administration (32.7 ± 10.1 ng ml⁻¹; t_max 28 ± 4.5 min) were significantly lower than those after intravenous administration (151.4 ± 28.2 ng ml⁻¹), while CSF concentrations achieved after intranasal administration (76.4 ± 14.0 ng ml⁻¹; t_max 28 ± 17.9 min) were significantly higher than those after intravenous administration (29.5 ± 7.4 ng ml⁻¹ t_max 60 min). The drug targeting index (DTI) of nasal route was 3.2, percent of drug targeting (DTP%) was 68.4%. These results showed that the E₂ must be directly transported from the nasal cavity into the CSF in rats. Finally, compared with E₂ inclusion complex, CS-NPs improved significantly E₂ being transported into central nervous system (CNS).     

PHARMACOKINETICS OF DA-125, A NEW ANTHRACYCLINE,AFTER INTRAVENOUS ADMINISTRATION TO URANYL NITRATE-INDUCED ACUTE RENAL FAILURE RATS OR PROTEIN--CALORIE MALNUTRITION RATS

The pharmacokinetics of DA-125 were compared after intravenous (i.v.) administration of the drug, 10 mg kg⁻¹, to control male Sprague--Dawley rats ( n=9) and uranyl nitrate-induced acute renal failure (U-ARF, n=12) rats, or male Sprague--Dawley rats fed on a 23% (control, n=8) or a 5% (protein--calorie malnutrition, PCM, n=9) protein diet. After i.v. administration of DA-125, almost ‘constant’ plasma concentrations of M1, M2, and M4 were maintained from 1--2 h to 8--10 h in all rat groups due to the continuous formation of M2 from M1 and M4 from M3. The plasma concentrations of M3 were the lowest among M1--M4 for all rat groups due to the rapid and almost complete conversion of M3 to M4 and other metabolite(s). The AUC_t values of M1 (115 against 82·5 μg min mL⁻¹), M2 (33·0 against 23·6 μg min mL⁻¹), and M4 (26·3 against 15·1 μg min mL⁻¹) were significantly higher in the U-ARF rats than in the control rats. The percentages of i.v. dose excreted in 24 h urine as M1 (under the detection limit against 0·316%), M2 (under the detection limit against 5·58%), and M4 (0·0174 against 0·719%)---expressed in terms of DA-125---were significantly lower in the U-ARF rats than in the control rats, and this could be due to the decreased kidney function in the U-ARF rats. However, the percentages of i.v. dose recovered from the GI tract at 24 h as M1 (0·0532% against under the detcction limit), M3 (0·0286% against under the detection limit), and M4 (0·702% against 0·305%)---expressed in terms of DA-125---were significantly greater in the U-ARF rats than in the control rats. All U-ARF rats had ascites, but the concentrations of M1 (0·0320 μg mL⁻¹), M2 (0·0265 μg mL⁻¹), M3 (under the detection limit), and M4 (0·032 μg mL⁻¹) in the ascites from one rat were almost negligible. The plasma concentrations and most of the pharmacokinetic parameters of M1, M2, and M4 were not significantly different between the PCM rats and their control rats.     

Assessment of effect of food,gender, and intra-subject variability in the pharmacokinetics of avitriptan

The objectives of this study were to assess the effect of food and gender on the pharmacokinetics of avitripan. A group of 12 healthy men and 12 healthy women was administered a single 50 mg dose of avitriptan capsule under fasting conditions and 5 min after a high-fat breakfast. The two treatments were repeated in a replicate design to assess the intra-subject variability in the pharmacokinetics of avitriptan under fasted and fed conditions. There was a 1 week washout between treatments. Serial blood samples were collected over 24 h after dosing and analyzed by a validated HPLC method for avitriptan. The mean (SD) peak concentrations (C_max) were 168 (86.4) ng mL⁻¹ in the fasted condition and 57.3 (34.8) ng mL⁻¹ in the fed condition in males and females combined. The corresponding areas under the plasma concentration curve (AUC) were 335 (162) and 185 (64.5) ng h mL⁻¹, respectively. Both C_max and AUC were significantly reduced in the fed condition. In addition, the time to peak concentration (t_max) was significantly delayed from a median of 45 min to 2 h after the high-fat breakfast. The clinical significance of this food effect is unclear at the present time. There were no gender differences nor a gender by food interaction in the pharmacokinetics of avitriptan. The intra- and inter-subject variability (%CV) in the C_max and AUC of avitriptan in the fasted and fed conditions ranged from 10 to 60% in male and female subjects. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration

Deacetyl diltiazem (M₁) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M₁ was administered as a single 5 mg kg⁻¹ dose intravenously (iv) to New Zealand white rabbits (n = 5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M₁ and its metabolites were determined by HPLC. The results showed that the only quantifiable basic metabolite in the plasma was deacetyl N-monodesmethyl DTZ (M₂). The t_1/2 and AUC of M₁ and M₂ were 2.1±0.5 and 3.0±1.1 h, and 1300±200 and 240±37 ng h mL⁻¹, respectively. The Cl and Cl_r of M₁ were 60±10 and 0.81±0.63 mL min⁻¹ kg⁻¹, respectively. M₁ significantly decreased blood pressure (SBP and DBP) for up to 1 h post-dose (p <0.05), but had no significant effect on the heart rate (p >0.05). The E_max and EC₅₀ as estimated by the inhibitory sigmoidal E_max model were 20±18% 620±310 ng mL⁻¹, respectively for SBP; 20±8.3% and 420±160 ng mL⁻¹ for DBP. © 1998 John Wiley & Sons, Ltd.     

6β-纳曲醇单次和连续肌内注射给药在犬体内的药代动力学

研究6β-纳曲醇单次和连续肌内注射给药在犬体内的药代动力学。Beagle犬 (n = 4) 肌内注射6β-纳  曲醇0.2 mg·kg⁻¹, 每日1次, 连续7日。用反相高效液相-电化学检测法测定血浆6β-纳曲醇浓度。Beagle犬单次 (第一次) 及连续给药 (最后一次) 后的血药浓度经时变化过程均符合血管外给药一级吸收二室模型 (R² > 0.999), 药代动力学参数分别为t_1/2α (0.26 ± 0.23) 和 (0.19 ± 0.18) h, t_1/2β (4.77 ± 1.65) 和 (5.79 ± 1.50) h, C_max (81.65 ± 5.61) 和 (79.82 ± 10.5) ng·mL⁻¹, t_peak (0.27 ± 0.07) 和 (0.18 ± 0.08) h, CL_s (1.20 ± 0.06) 和 (1.12 ± 0.07) L·kg⁻¹·h⁻¹, V/F_c (1.94 ± 0.15) 和 (2.10 ± 0.27) L·kg⁻¹, AUC_0−t (166.82 ± 7.68) 和 (173.23 ± 9.49) ng·h·mL⁻¹。第一次和最后一次给药的药代动力学参数无显著性差异 (P > 0.05)。连续给药期间, 血药峰浓度和谷浓度的平均值分别为  (79.03 ± 10.3) 和 (1.50 ± 0.93) ng·mL⁻¹。结果显示, 6β-纳曲醇在犬体内的药物代谢过程符合一级吸收二室模型, 得到了相应的药代动力学参数; 连续给药对原形药物代谢过程基本无影响。     

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

A study was conducted to (i) characterize the multiple-dose pharmacokinetics of oral montelukast sodium (MK-0476), 10 mg d⁻¹ in healthy young subjects (N =12), (ii) evaluate the pharmacokinetics of montelukast in healthy elderly subjects (N =12), and (iii) compare the pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects. Following oral administration of montelukast sodium, 10 mg d⁻¹ (the therapeutic regimen for montelukast sodium) for 7 d, there was little difference in the plasma concentration–time profiles of montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL⁻¹ on days 3–7, indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio was 1·14, indicating that this dose regimen results in a 14% accumulation of montelukast. In elderly subjects, mean values of plasma clearance (Cl), steady-state volume of distribution (V_ss), plasma terminal half-life (t_1/2), and mean residence time in the body (MRT^IV) following a 7 mg intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30·8 mL min⁻¹, 9·7 L, 6·7 h, and 5·4 h, respectively. Following a 10 mg oral dose, the bioavailability of montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC_0→∞, C_max, t_max, and t_1/2, and the mean plasma concentration–time profile of montelukast in the elderly, were generally similar to those in young subjects, indicating that age has little or no effect on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age. © 1997 John Wiley & Sons, Ltd.     

PHARMACOKINETICS AND FOOD INTERACTION OF MK-462 IN HEALTHY MALES

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5–90 μg kg⁻¹of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 μg kg⁻¹ are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 μg kg⁻¹. The values of the plasma clearance (CL), steady-state volume of distribution (V_ss), plasma terminal half-life (t_½), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min⁻¹, 140 L, 1·8 h, and 1·7 h, respectively, and remained essentially constant over the dosage range of 10–60 μg kg⁻¹ of IV MK-462. However, as the dose increased from 60 to 90 μg kg⁻¹, the mean value of the apparent CL decreased from 1376 to 807 mL min⁻¹. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the V_ss value of MK-462 remained essentially constant over the dosage range of 10–90 μg kg⁻¹ of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CL_d=2028 mL min⁻¹, and mean transit time in the peripheral tissues (MTT_T )=0·74 h. The mean values of AUC, C_max, t_max, and apparent t_½ of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng·h mL⁻¹, 77 ng mL⁻¹, 1·6 h, and 1·8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by ≈20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of C_max and apparent t_½ of MK-462.     

The influence of food on the disposition of the antiepileptic rufinamide in healthy volunteers

The effect of food on the pharmacokinetics of the antiepileptic rufinamide was investigated in healthy volunteers. Twelve subjects were treated with single per-oral doses of 600 mg of rufinamide after overnight fasting or a fat and protein rich breakfast. Mean (±S.D.) areas under the plasma concentration–time curves (AUCs) of the unchanged compound were 57.2 (16) μg mL⁻¹ h when given to the fasted volunteers and 81.7 (22.2) μg mL⁻¹ h (p = 0.0001) when given after the breakfast. The average AUC was increased by 44% when rufinamide was given with food and the maximum concentration (C_max) by about 100%. The time at which C_max was reached (t_max) was shorter (8 h in fasted conditions and 6 h in fed after breakfast); the terminal half-life was not influenced by concomitant intake of food. © 1998 John Wiley & Sons, Ltd.     

Quantification of three beta‐lactam antibiotics in breast milk and human plasma by hydrophilic interaction liquid chromatography/positive‐ion electrospray ionization mass spectrometry

The use of cephalosporins during breast feeding raises several issues, including the risk of drug exposure through breast milk for the infant. In this paper, a hydrophilic interaction liquid chromatography/positive ion electrospray mass spectrometric assay (HILIC/ESI‐MS) was developed for the quantitation of cefuroxime, cefoxitin, and cefazolin in breast milk and human plasma. The assay was based on the use of small sample size, 25 μL of biological samples, following acetonitrile precipitation of proteins and filtration that enabled injection into the HILIC/ESI‐MS system. All analytes and the internal standard, alfuzosin, were separated by using a ZIC®‐HILIC analytical column (150.0 × 2.1 mm i.d., particle size 3.5 µm, 200 Å) with isocratic elution. The mobile phase was composed of a 6% 12.5 mM ammonium acetate water solution in acetonitrile and pumped at a flow rate of 0.25 mL min^‐1. The assay was linear over a concentration range of 0.2 to 5 µg mL^‐1 and 0.4 to 20 µg mL^‐1 for all the analytes in breast milk and in human plasma, respectively. Intermediate precision was found to be less than 4.2% over the tested concentration ranges. A run time of less than 12 min for each sample made it possible to analyze a large number of biological samples per day. The method is the first reported application of HILIC in the analysis of antibiotics in breast milk and human plasma and it can be used to support a wide range of clinical studies. Copyright © 2016 John Wiley & Sons, Ltd.     

Unexpected effect of concomitantly administered curcumin on the pharmacokinetics of talinolol in healthy Chinese volunteers

Objective To investigate the effect of concomitantly administered curcumin on the pharmacokinetics of the β1 adrenoceptor blocker talinolol. Methods The study was conducted in a self-controlled, two-period experiment with a randomized, open-labeled design, using 12 healthy volunteers and a wash out period of 1 week between the administration of a single oral dose of 50 mg talinolol and the concomitant administration of curcumin (300 mg day⁻¹ for 6 days) and a single oral dose of 50 mg talinolol on the seventh day. Concentrations of talinolol were measured in plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. Non-compartmental analysis was used to characterize talinolol plasma concentration-time profiles, all pharmacokinetic parameters were calculated using DAS (ver. 2.0) software, and comparisons of mean values were analyzed by the Wilcoxon signed rank test. Differences were considered to be significant at p < 0.05 (two-sided test). Results The consumption of curcumin for 6 days reduced the area under the curve (AUC) from predose to infinity () of talinolol from 1860.0 ± 377.9 to 1246.0 ± 328.2 ng.h mL⁻¹, the highest observed concentration values (C_max) were significantly decreased from 147.8 ± 63.8 to 106.4 ± 39.9 ng mL⁻¹, and the CL/F was increased from 27.9 ± 5.5 to 43.1 ± 13.4 L.h⁻¹ (p < 0.05). There was no significant difference in sampling time for C_max (t_max) and elimination half-life (t_1/2) values between the two periods (p > 0.05). The interindividual variability in AUC_0–60 and C_max of talinolol was comparable in two study periods; the coefficient of variance (CV) of AUC_0–60 and C_max was 26 and 40% after curcumin versus 21 and 43% after talinolol alone, respectively. Conclusion We suggest that the reduced bioavailability of talinolol is most probably due to the low intraluminal curcumin concentration, or possibly due to the upregulation of further ATP-binding cassette transporters, such as MRP2, in different tissues.     

The influence of moderate and chronic exercise training on the pharmacokinetics of procainamide and N-acetylprocainamide

The effect of moderate and prolonged exercise on the disposition and metabolism of drugs has not been extensively examined. The present study examined the effect of exercise training on the pharmacokinetics of procainamide and its active metabolite, N-acetylprocainamide. Male Sprague Dawley rats were randomly assigned to three testing groups: (1) sedentary, (2) 4 weeks of exercise training and (3) 8 weeks of exercise training. Treadmill speed and exercise duration were gradually increased, reaching a final rate of 24 m min⁻¹ for an hour by the end of the 4-week or 8-week period. Sedentary and exercise trained rats received a single i.p. dose of procainamide (100 mg kg⁻¹). Serial blood samples were collected over a 10 h period and plasma samples were analysed by an UV-HPLC method. Noncompartmental analysis was performed to estimate the pharmacokinetic parameters. The t_1/2 of procainamide was significantly (p <0.05) higher in the 8 week exercise group (331 min) as compared to the sedentary group (77 min). In addition, there was a significant reduction in the amount of N-acetylprocainamide formed after 8 weeks of exercise (AUC_NAPA=739 ng mL⁻¹ min⁻¹). Results of this study suggest that prolonged exercise (8 weeks of training) alters the pharmacokinetics of procainamide by modifying the amount of active metabolite formed. © 1998 John Wiley & Sons, Ltd.     

The influence of plasma butyrylcholinesterase concentration on the in vitro hydrolysis of cocaine in human plasma

In humans, the plasma enzyme butyrylcholinesterase, BChE (EC 3.1.1.8), mediates the in vivo plasma hydrolysis of cocaine to the pharmacologically inactive metabolite ecgonine methyl ester, EME. This enzyme has been purified from human plasma to investigate the potential as a treatment for cocaine intoxication. Cocaine (2.1 μg mL⁻¹) was incubated in plasma with a BChE concentration in the normal range (3.02 μg mL⁻¹) and in plasma with enhanced BChE concentrations of 9.14, 20.8 and 37.8 μg mL⁻¹, respectively for time periods up to 120 min. Cocaine and the hydrolytic products, ecgonine methyl ester and ecgonine, were quantified simultaneously by gas chromatography-mass spectrometry (GC-MS). The enhancement of plasma BChE concentration resulted in a dramatic increase in the rate of hydrolysis of cocaine. There was a stoichimetric conversion of cocaine to the inactive hydrolysis product, ecgonine methyl ester. Accordingly, the half-life of cocaine in plasma decreased significantly with enhanced BChE concentration. At plasma BChE concentrations of 3.02, 9.14, 20.8 and 37.8 μg mL⁻¹, half-life values of 116, 35.8, 21.4 and 9.0 min, respectively were observed. The marked reduction in cocaine half-life provides evidence supporting the potential therapeutic use of BChE for the treatment of cocaine intoxication. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetic changes of M1, M2, M3 and M4 after intravenous administration of a new anthracycline,DA-125, to rats pretreated with phenobarbital, 3-methylcholanthrene,chloramphenicol, or SKF-525A

The pharmacokinetics of M1–M4, the metabolites of a new anthracycline antineoplastic agent, DA-125, were compared after intravenous (IV) administration of DA-125, 15 mg kg⁻¹, to rats pretreated with enzyme inducers, such as phenobarbital (PBT, n = 14) and 3-methylcholanthrene (MCT, n = 15), or enzyme inhibitors, such as SKF-525A (SKT, n = 11) and chloramphenicol (CMT, n = 15), and to their control rats (n = 15 for PBC, CMC or SKC, and n = 11 for MCC). After IV administration of DA-125, the plasma concentrations of both M1 and M2 declined slowly from 1 to 2 h onwards to 8 h in all groups of rats due to the continuous formation of M2 from M1. The AUC_{0–8 h} of M1 (47.1 versus 7.85 μg min mL⁻¹) and M2 (20.7 versus 44.3 μg min mL⁻¹) decreased significantly in the PBT group compared to those in the PBC group. However, the corresponding value of only M1 (74.6 versus 89.9 μg min mL⁻¹) decreased significantly in the MCT group. The above data indicate that metabolism of M1 is increased by pretreatment with both PB and 3-MC, and that of M2 with PB, but not with 3-MC. The AUC_{0–8 h} of both M1 (126 versus 78.5 μg min mL⁻¹) and M2 (69.2 versus 44.3 μg min mL⁻¹) increased significantly in the SKT group compared to the SKC group. However, the corresponding values were not significantly different between CMC and CMT groups. The above data indicate that the metabolism of both M1 and M2 is inhibited by pretreatment with SKF-525A, but not with CM. © 1998 John Wiley & Sons, Ltd.