COMPARATIVE ABSORPTION OF BISMUTH IN SPRAGUE–DAWLEY RATS FOLLOWING ORAL ADMINISTRATION OF PREPARATIONS CONTAINING BISMUTH SUCROSE OCTASULFATE,BISMUTH SUBSALICYLATE,AND BISMUTH SUBCITRATE

The absorption of bismuth from De-Nol (bismuth subcitrate, DN), Pepto-Bismol (bismuth subsalicylate, PB) and bismuth sucrose octasulfate (BISOS) was examined in male Sprague–Dawley rats after a single oral dose of each compound (60 mg bismuth). Bismuth was analysed in blood, urine, kidney, brain, liver, and lung using graphite furnace atomic absorption spectrophotometry. Bismuth C_max averaged 18·4±11·6 ng mL⁻¹ for BISOS, 292±130 ng mL⁻¹ for DN, and 21·5±9·63 ng mL⁻¹ for PB. C_max was significantly lower for BISOS compared to DN (p <0·05) but not significantly different for BISOS compared to PB (p >0·05). Bismuth AUC was 1356±474 ng h⁻¹ mL⁻¹ for BISOS, 2129−452 ng h⁻¹ mL⁻¹ for DN, and 1824−919 ng h⁻¹ mL⁻¹ for PB, which indicated a lower extent of absorption from BISOS compared to DN. Kidney, liver, and lung levels of bismuth were also significantly lower for BISOS compared to DN (p <0·05). Bismuth urinary excretion was significantly lower for BISOS (0·04±0·02%) compared to DN (0·27±0·15%) but not significantly different compared to PB (0·07±·03%). These data suggest that the absorption of bismuth following oral administration of bismuth sucrose octasulfate is significantly lower than that from De-Nol and similar to that from Pepto-Bismol. © 1997 by John Wiley & Sons, Ltd.     

A LIMITED SAMPLING METHOD FOR THE ESTIMATION OF FLUNARIZINE AREA UNDER THE CURVE (AUC) AND MAXIMUM PLASMA CONCENTRATION (CMAX)

A limited sampling model has been developed for flunarizine following a 30 mg oral dose in epileptic patients who were receiving phenytoin or carbamazepine or both, to estimate the area under the curve (AUC) and maximum plasma concentration (C_max). The model was developed using training data sets from 30, 20, 15, or 10 patients at one or two time points. The equations describing the models for AUC using two time points (3 and 24 h) and C_max for the training data set of 30 subjects were AUC_predicted=11·1 C_{3 h}+121·4 C_{24 h}–157 (r =0·80) C_{max(predicted)}=0·036 AUC+42·9 (r =0·74) The model was validated on 64 patients who received flunarizine orally. The model provided reasonably good estimates for both AUC and C_max. The mean predicted AUC of flunarizine was 1230±717 ng h mL⁻¹, whereas the observed AUC was 1203±900 ng h mL⁻¹. The bias of the prediction was 2% and precision was 28%. The mean predicted C_max of flunarizine was 86±32 ng mL⁻¹ as compared to an observed mean C_max of 90±42 ng mL⁻¹. The bias and precision of the prediction were 4% and 24%, respectively. The method described here may be used to estimate AUC and C_max for flunarizine without detailed pharmacokinetic studies. © 1997 by John Wiley & Sons, Ltd.     

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.     

伏立康唑胶囊人体药动学及相对生物利用度研究

目的 研究健康受试者口服伏立康唑胶囊的药动学和相对生物利用度。方法 20名健康受试者随机服用伏立康唑受试胶囊剂和参比片剂各100 mg,用HPLC-MS/MS测定血浆中伏立康唑的浓度。结果 主要药动学参数,伏立康唑受试制剂与参比制剂的T_max分别为(0.75±0.15)和(0.84±0.25)h,C_max分别为(605.4±136.6)和(595.2±134.7)ng·mL^-1;t_1/2分别为(4.91±1.44)和(5.06±2.06)h,AUC_0-15分别为(1737.6±325.1)和(1750.6±352.8)ng·h·mL^-1。受试制剂与参比制剂的AUC_0-15和C_max经双单侧t检验,T_max经非参数检验,差异均无统计学意义。结论 统计学结果表明,2种制剂生物等效。     

THE INFLUENCE OF TIME OF ADMINISTRATION ON THE PHARMACOKINETICS OF A ONCE-A-DAY DILTIAZEM FORMULATION: MORNING AGAINST BEDTIME

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for C_min (mean (SD)=47·2 (25·8) against 39·6 (21·1) ng mL⁻¹, p=0·038), AUC_0–24 (2008 (814) against 1754 (714) ng h mL⁻¹, p=0·024), and AUC_0–48 (2662 (1244) against 2395 (238) ng h mL⁻¹, p=0·034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.     

AN INVESTIGATION OF THE DOSE PROPORTIONALITY OF DEFLAZACORT PHARMACOKINETICS

The dose proportionality of deflazacort was assessed following single-dose oral administration at doses of 3, 6, and 36 mg to 24 healthy young adult volunteers. The active metabolite of deflazacort (21-desacetyl deflazacort) was monitored in plasma using a sensitive, semi-microbore liquid chromatographic method. C_max averaged 10·4±5·0, 19·8±7·5, and 132·6±52·5 ng mL⁻¹ for the 3, 6, and 36 mg doses, respectively. AUC(0–∞) averaged 38·5±37·1, 64·9±20·8, and 411·7±148·5 ng h mL⁻¹ for the same three doses, respectively. Elimination half-life ranged from 1·9±0·5 h at the 6 mg dose to 2·4±1·5 h at the 36 mg dose. Regression analyses of dose versus C_max and AUC(0–∞) yielded intercepts which were not significantly different from zero (p>0·05) and slopes which were significant (p<0·05). Regression analysis of dose versus apparent oral clearance yielded a slope which was not significantly different from zero (p>0·05). These data indicate that deflazacort exhibits dose-proportional pharmacokinetics.     

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.     

PERCUTANEOUS ABSORPTION AND DISPOSITION STUDIES OF METHOTREXATE IN RABBITS AND RATS

The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5·9 ± 2·8 ng mL⁻¹) which appeared at ∼2 h postdose and declined with the elimination half-life of 4·48 ± 1·74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49·0 ± 19·8 μg g⁻¹), muscle (12·7 ± 3·3 ng g⁻¹), and SF (19·2 ± 10·1 ng g⁻¹) underneath the dosed stifle joint were significantly higher (p <0·05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (∼59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1·8 and 2·6 times higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26·3 ± 8·3 and 48·8 ± 5·2 mg, respectively. A significant enhancer effect of N,N -diethyl-n -toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed (p < 0·05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a linear calibration curve (r > 0·999) over the range of 2–50 ng mL⁻¹, quantitation limit of 0·5 ng mL⁻¹, and mean recovery of ∼87% was used for the quantitation of MTX in the tissue and fluid samples. © 1997 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.     

Comparative bioavailability of josamycin,a macrolide antibiotic,from a tablet and solution and the influence of dissolution on in vivo release

The bioavailability of josamycin from a tablet formulation (2 × Josacine® 500 mg tablets) was investigated and compared with the bioavailability of a solution (containing 1 g drug and buffered at pH 4.0) following administration to six healthy human volunteers. Bioavailability profiles for the solution indicated that the drug was inherently rapidly absorbed with a mean C_max of 1.64±0.67 mg L⁻¹ attained at a mean t_max of 0.39±0.08 h. The AUC_0–last was 1.510±0.687 mg h L⁻¹. Bioavailability was significantly lower from the tablets than from the solution. Highly variable serum concentration–time profiles were obtained from the tablets and C_max values ranged from 0.05 to 0.71 mg L⁻¹ with a t_max range of 0.33–2.0 h. AUC_0–last values ranged from 0.03 to 0.95 mg h L⁻¹. Dissolution of josamycin from the tablets was generally unaffected at low pH (pH 1.2–5.0), but, rather, limited predominantly by tablet disintegration. However, dissolution was increasingly limited as the pH increased from 5.0 to 9.0. Besides poor disintegration, the particularly low intrinsic dissolution rate and solubility of josamycin at these pH values is likely to further reduce the dissolution rate. Comparison of the solution and tablet serum concentration–time profiles suggests that the absorption of josamycin from the tablets was dissolution rate limited. This is supported by the in vitro dissolution–pH topogram, which suggests that dissolution will be particularly rate limiting if dissolution of whole or parts of tablets occurs in gastro-intestinal fluid above pH 5.0. © 1998 John Wiley & Sons, Ltd.     

The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon-tetrachloride-intoxicated rats

The relationships between the pharmacokinetic behaviour of glycyrrhizin and its restorative effect for hepatic function were investigated in patients with chronic hepatitis and in rats chronically treated with carbon tetrachloride (CCl₄-treated rats). In patients, the restorative effects in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were 62·2±7·4 and 64·4±7·5%, respectively, after daily 80 mg intravenous (i.v.) doses of glycyrrhizin for 2 weeks, and 63·1±19·1 and 68·7±15·2% after 120 mg doses. The present work suggests that the threshold plasma glycyrrhizin concentration for sufficient effect is near 5 μg mL⁻¹. In rats, the total body clearance (Cl_tot) for glycyrrhizin in the CCl₄-treated rats after i.v. administration of glycyrrhizin (5 mg kg⁻¹ dose) was three-tenths of that of the control, and the t_1/2 for glycyrrhizin was 3·4-fold longer than that of the control. A good correlation was observed between Cl_tot and AST (r=−0·838) or ALT (r=−0·873) activity in both rats. When glycyrrhizin was administered intraperitoneally (i.p.) three times a week for 2 weeks, both the AST and ALT activities in the CCl₄-treated rats showed a greater improvement than for a 10 mg kg⁻¹ dose. Furthermore, the finding on the threshold plasma concentration in patients as above was also supported from the results of the experiments in rats. © 1997 John Wiley & Sons, Ltd.     

Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys

Abstract— The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[N^α-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg^?1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vd_ss = 3·86±1·04 L kg^?1, plasma clearance = 2·22 ± 0·39 L kg^?1, and AUC= 1445 ± 266 ng h mL^?1. After 30 mg kg^?1 oral dose, maximum plasma concentration, t_max and AUC of YM-21095 were 28·8 ± 9·6 ng mL^?1, 0·25 h and 23·6 ± 7·7 ng h mL^?1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg^?1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg^?1 oral dose to monkeys was 71·8 ± 41·5 ng mL^?1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.     

Design and evaluation of enteric-coated tablets for rifampicin and isoniazid combinations

In order to improve the bioavailability of rifampicin (RIF) from rifampicin and isoniazid (INH) combination formulations, the physicochemical characteristics of RIF, stability of RIF in different pH buffers in the presence of INH, as well as the effect of particle size of RIF materials on the dissolution rate were investigated. On the basis of the above examinations, enteric-coated tablets for RIF and INH combinations were designed and prepared. RIF showed low solubility and high apparent distribution coefficient in the intestinal pH (pH 4.0–7.4). With the decrease in pH, the degradation of RIF increase and the presence of INH deepen the degradation. Enteric-coated tablets were prepared after grinding the RIF materials by dry granulation technique. The pharmacokinetics of RIF and INH of self-made enteric-coated tablets in dogs were studied by comparing with the reference tablets. The AUC_0–48 of RIF in both reference and test tablets were 304.77 ± 42.27 and 353.79 ± 31.63 µg·h·mL^?1, respectively. The AUC_0–48 of INH in both reference and test tablets were 17.14 ± 8.59 and 19.62 ± 10.57 µg·h·mL^?1, respectively. Enteric-coated tablets may minimize the decomposition of RIF in gastrointestinal tract and improve the bioavailability.     

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.     

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.     

多剂量口服马来酸曲美布汀缓释片的药动学及生物等效性研究

目的 研究多剂量口服马来酸曲美布汀缓释片在中国健康人体内的药动学特征和生物等效性。方法 26名健康男性志愿者随机交叉多剂量早晚口服马来酸曲美布汀缓释片受试制剂或参比制剂300 mg,每日2次,连续6 d。采用HPLC-MS/MS测定血浆中曲美布汀和N-去甲基曲美布汀浓度,用DAS2.1药动学程序计算药动学参数,并进行生物等效性评价。结果 多剂量口服马来酸曲美布汀受试和参比制剂后,血浆曲美布汀C_max分别为(35.668±22.196),(33.022±16.077)ng·mL^-1,t_max分别为(3.154±1.875),(0.365±9.946)h,t_1/2分别为(20.793±13.305),(16.989±4.707)h,AUC_ss分别为(252.075±150.358),(224.106±95.405)ng·h·mL^-1;血浆N-去甲基曲美布汀C_max分别为(1 571.809±823.169),(1 623.535±536.813)ng·mL^-1,t_max分别为(-0.250±11.259),(2.481±1.237)h,t_1/2分别为(9.796±2.450),(9.220±2.009)h,AUC_ss分别为(11 254.863±5 746.620),(10 911.059±4 111.751)ng·h·mL^-1。受试制剂和参比制剂主要药动学参数均无显著性差异。结论 马来酸曲美布汀受试制剂与参比制剂具有生物等效性。     

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.     

THE EFFECT OF FOOD ON THE PHARMACOKINETICS OF THE BICALUTAMIDE (‘CASODEX’) ENANTIOMERS

‘Casodex’ (bicalutamide) is an orally active, non-steroidal, pure antiandrogen; it is a racemate with antiandrogenic activity residing predominantly in the (R)-enantiomer. Healthy male volunteers (n =15) were administered single oral doses of bicalutamide (50 mg) after food and after fasting as part of a three-treatment, three-period, randomized cross-over study, with a 9 week washout. After fasting, plasma concentrations of (R)-bicalutamide were much higher than those of (S)-bicalutamide; the mean (R)-enantiomer C_max (734 ng mL⁻¹) was about nine times higher than the (S)-enantiomer value (84 ng mL⁻¹). The corresponding t_max values were 19 and 3 h for (R)- and (S)-bicalutamide respectively. Elimination of (R)-bicalutamide from plasma was monoexponential and slow (t_1/2=5·8 d). Elimination of (S)-bicalutamide was biphasic in some volunteers but monophasic in others (terminal t_1/2=1·2 d; n =11). There was no significant effect of food on AUC, t_max, or t_1/2 data for either enantiomer. The observed slightly higher values of C_max for (R)-bicalutamide (14%) and (S)-bicalutamide (19%), when dosing with food, achieved statistical significance. However, differences of this magnitude are unlikely to be of any clinical relevance. These data indicate that ‘Casodex’ can be taken without reference to meal-times; this may be of particular relevance for its indication in a disease of the elderly. © 1997 John Wiley & Sons, Ltd.     

Steady-state pharmacokinetics and bioequivalence study of quetiapine fumarate film-coated tablets 300 mg in adult schizophrenic patients

Quetiapine is a dibenzothiazepine derivative approved for the treatment of schizophrenia and related psychoses. The objective of the present study was to design and evaluate the bioequivalence between quetiapine fumarate film-coated tablets of Dr. Reddy’s Laboratories Ltd., Hyderabad, India (test) and Seroquel^® tablets (containing quetiapine) of AstraZeneca Pharmaceuticals LP Wilmington, DE, USA (reference). It was a two-way crossover steady-state multiple dose study in 54 adult schizophrenic patients under fasting conditions. Quetiapine was analyzed in plasma samples by using a validated liquid chromatographic mass spectrometry (LC-MS/MS) method. The pharmacokinetic parameters were estimated by noncompartmental method and mean (±SD) of C_max,ss (ng/mL) for test and reference products were 1436.5 (±810.2) and 1413.1 (±905.5), respectively. The mean (±SD) of AUC_τ,ss (ng·h/mL) for test and reference products were 6949.8 (±3879.8) and 6532.2 (±4279.4), respectively. The ratio of least square means and its 90% confidence interval for C_max,ss and AUC_τ,ss were found to be within bioequivalence limits 80.00–125.00%. In conclusion, test product was bioequivalent to the reference product in terms of both rate and extent of absorption under steady-state conditions.