Ibopamine (SK&F 100168) pharmacokinetics in relation to the timing of meals.

The effect of the timing of a standard meal relative to a single oral dose of 200 mg ibopamine, on the appearance of its pharmacologically active metabolite, epinine, in plasma was investigated in a randomised crossover study in 12 healthy volunteers. After a 12 h fast, ibopamine was administered either in the fasting state (no meal), or 1 h before, 0.5 h before, immediately after, 2 h after or 3 h after a standardised meal. Blood samples taken immediately before and at intervals for 3 h after dosing were analysed for free epinine. Maximum concentration (Cmax), time to Cmax(tmax), and area under the concentration-time curve (AUC) for free epinine in plasma were calculated. When compared with the fasting state, Cmax and AUC0-3h were significantly reduced when ibopamine was given immediately after or 2 h after a meal. AUC was also reduced for ibopamine given 0.5 h before a meal. tmax was significantly delayed when ibopamine was given immediately after, or 2 or 3 h after a meal. Thus, administration of ibopamine with or shortly after a meal reduced the rate and extent of appearance of free epinine in plasma. The clinical significance of reduced epinine levels on acute dosing in the presence of food is unknown.     

The relative bioavailability study and fasting and fed states pharmacokinetics of bicalutamide 50-mg tablets in healthy Chinese volunteers

The aim of this study was to evaluate the bioequivalence of a new generic formulation of bicalutamide 50-mg tablets (test) and the available branded formulation (reference) to comply with regulatory criteria for marketing of the test product in China. This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in 40 healthy male volunteers and consisted of separate fasting and fed phases. A single oral dose of the test or reference formulation was followed by a 6-week washout period, after which subjects received the alternative formulation. Blood samples were collected before dosing and at 0.5, 1, 2, 4, 8, 12, 15, 24, 30, 36, 48, 72, 144, 288, 432 and 576?h after dosing. Plasma samples were separated and assayed for bicalutamide using a selective and sensitive HPLC method with UV detection. The fasting and fed states pharmacokinetic parameters AUC0-576?h, AUC0-∞, Cmax, tmax and t1/2 were determined from plasma concentration-time profile of both formulations. The formulations were considered bioequivalent when the 90% CIs of the geometric mean ratios (test:reference) for Cmax and AUC0-576?h were within the regulatory range of 80-125%. There were no significant increases in bicalutamide Cmax, AUC0-576?h or tmax for either formulation in the fed phase compared with the fasting phase. In both the fasting and fed portions of the study, the 90% CIs for the ratio (test:reference) of log-transformed Cmax and AUC0-576?h were within the acceptance range for bioequivalence.     

Single- and multiple dose pharmacokinetics of lonidamine in patients suffering from non-small-cell lung cancer.

Pharmacokinetic studies of lonidamine (1-[2,4-dichlorobenzyl]- 1H- indazole- 3-carboxylic acid, Doridamina: CAS 50264-69-2) in humans showed a wide variation of the plasma concentration-time profiles following a single peroral dose of 300 mg (Cmax between 6.5 and 40.9 micrograms/ml, tmax between 0.75 and 5.5 h). In order to investigate single and multiple dose pharmacokinetics after peroral administration of this chemotherapeutic compound, a study was performed involving 12 patients with non-small-cell malignancies of the lungs. Plasma and urinary concentration profiles were analyzed for determination of the pharmacokinetic parameters for lonidamine after single dose administration and in the steady state. In addition, age dependency and the presence of liver induction or inhibition was evaluated. Results indicate that steady state was reached after 2 dosing intervals of 12 h and no changes in liver metabolism or age dependent pharmacokinetics could be revealed after 4 days of multiple dose treatment.     

Pharmacokinetics of licarbazepine in healthy volunteers: single and multiple oral doses and effect of food

Two studies characterized single- and multiple-dose pharmacokinetics of licarbazepine immediate-release tablets and food effects on single-dose pharmacokinetics. In 1 study, 12 volunteers received 500 mg licarbazepine on day 1, 500 mg bid on days 3 to 6, and 500 mg on day 7. In the second study, 12 subjects received one 500-mg licarbazepine dose under fasted and fed conditions. After multiple dosing, geometric mean (%CV) Cmax ss, Cmin ss, and AUCtau were 77.6 micromol/L (18), 45.3 micromol/L (25), and 747 h.mol/L (19), respectively, with a tmax of 2 hours. Mean half-lives were 9.3 and 11.3 hours for single and multiple dosing, respectively. Food had no clinically significant effect on single-dose pharmacokinetics. Half-life ( approximately 10 hours) and low intersubject variability in main pharmacokinetic parameters were similar under fasted and fed conditions. Median tmax increased from 1.5 to 2.5 hours with food. Licarbazepine is well tolerated and has predictable pharmacokinetics.     

6-Thioguanine in children with acute lymphoblastic leukaemia: influence of food on parent drug pharmacokinetics and 6-thioguanine nucleotide concentrations

AIMS: Since relatively little is known about the pharmacokinetics of 6-thioguanine (6TG) in children receiving 6-thioguanine for maintenance therapy of acute lymphoblastic leukaemia (ALL), we studied plasma drug concentrations under standardized conditions and investigated the effect of food on parent drug pharmacokinetics and the accumulation of the active metabolites 6-thioguanine nucleotides (6-TGNs) in red cells. METHODS: Single oral doses of 40 mg of 6-TG were administered both in the fasting and fed state to children with ALL. Pharmacokinetic sampling was performed up to 6 h post dose. Daily oral doses of 40 mg m(-2) of 6-TG were administered both fasting and after food over two 4 week periods. Twice weekly samples were taken for metabolite concentrations. The study design was cross-over with each child receiving dosing in either fasted or after food over a 4 week period in each phase. RESULTS: Eleven patients were studied. A wide interindividual variation in Cmax (median 313 pmol ml(-1), range 51-737) and AUC (median 586 pmol ml(-1) h, range 156-1306) was observed in the fasted state. Concomitant food administration resulted in a significant reduction in Cmax (median 71 vs 313 pmol ml(-1), P = 0.006, CI from 36 to 426), AUC (median 200 vs 586 pmol ml(-1) h, P = 0.006, 95% CI from 109 to 692), and time to reach Cmax (median 1.5 vs 3 h, P = 0.013, 95% CI from 0.74 to 2.73). There was no difference in the steady state concentration of red cell 6-TGNs observed after a 4 week period of 6-TG administered fasting or after food. CONCLUSIONS: Children with ALL demonstrate significant interindividual variation in 6-TG pharmacokinetics. Although there would appear to be a reduction in parent drug Cmax and AUC with food there was no difference in 6-TGN concentrations after 4 weeks of 6-TG. Taking the drug on an empty stomach may not be necessary.     

Steady state relative bioavailability and pharmacokinetics of oral propranolol in black and white North Americans

The steady state bioavailability and pharmacokinetics of propranolol over two consecutive dosing intervals were investigated in 18 black and 10 white normal volunteers following the administration of 20 mg of a test and reference oral dosage form, respectively, every 6 h. There were no differences (p greater than 0.05) between dosage forms in the mean (n = 28) area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax) or time to Cmax (tmax) for propranolol or its active metabolite, 4-hydroxypropranolol. However, as a group blacks had lower plasma concentrations of propranolol during the second dosing interval (AUC-2 and Cmax-2, respectively) were significantly (p less than 0.05) lower in blacks, but there were no ethnic differences (p greater than 0.05) in tmax. The mean AUC and Cmax for the 4-hydroxylated metabolite during both dosing intervals were significantly (p less than 0.05) lower in blacks. Mean oral clearances of propranolol, assuming complete absorption, (range: 42.1-54.5 ml min-1 kg-1) were similar (p greater than 0.05) in each racial group. There were no substantial changes in heart rate or blood pressure in blacks or whites following propranolol administration. These data suggest that for oral propranolol, blacks have different absorption and disposition characteristics than whites.     

Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome.

The pharmacokinetic profile and biochemical efficacy of idrapril calcium, a novel angiotensin converting enzyme (ACE) inhibitor, were evaluated in healthy volunteers after multiple dosing for 5 days at the doses of 100, 200 and 400 mg twice daily. The study was conducted as a double-blind, cross-over comparison of idrapril calcium against placebo. Plasma concentrations of idrapril were determined by an indirect enzymatic method. Urinary concentrations were measured by reverse phase high performance liquid chromatography (h.p.l.c.). Plasma samples were also analysed for ACE activity. The pharmacokinetics of idrapril calcium did not change significantly between day 1 and day 5. The values of Cmax and AUC were dose-related over the range of doses tested; tmax was 3-4 h and apparent elimination half-life was 1.4-1.6 h. Plasma ACE activity was maximally inhibited (94-96%) at all dose levels and remained more than 80% depressed from 2 to at least 6 h after idrapril calcium. Although the maximum effect was not dose-related, the duration of inhibition showed some dose-dependency, ACE activity returning to 56, 45 and 29% of the basal value 12 h after the 100, 200 and 400 mg doses, respectively. There were no clinically significant adverse events experienced by the volunteers. No dose-related effects on blood pressure or heart rate were observed. There were no changes in clinical pathology tests, urine analyses or electrocardiograms after dosing with idrapril calcium. Idrapril calcium, the prototype of a new class of ACE inhibitors, appears to be well-tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fosinopril/hydrochlorothiazide: single dose and steady-state pharmacokinetics and pharmacodynamics

AIMS: Fosinoprilat, the active product of fosinopril, is eliminated by an hepatic pathway in addition to the renal pathway shared by other angiotensin converting enzyme inhibitors (ACEIs). This study aimed to determine whether impaired renal function affects the pharmacokinetics and pharmacodynamics of a combination of fosinopril and hydrochlorothiazide (HCTZ). METHODS: The study had a parallel-group design comparing patients with renal impairment and body-mass-index-matched normal controls. The study was done in a University clinic in 13 patients with renal impairment (mean creatinine clearance 55.7+/-15.6 ml min-1 1.73 m-2 ) and 13 age-, sex-, and body-mass-index-matched normal controls (mean creatinine clearance 102.4+/-8.9 ml min-1 1.73 m-2 ). All patients and normal controls received fosinopril sodium 20 mg and HCTZ 12.5 mg as a daily oral administration on days 1-5. Non-compartmental pharmacokinetic parameters of fosinoprilat and HCTZ were determined from blood and urine samples obtained over 48 h starting on Day 1 (single dose) and Day 5 (steady state): maximum serum concentration (Cmax ), time to maximum serum concentration (tmax ), area under the serum concentration-time curve during the dosing interval (AUC), cumulative urinary excretion (CUE) and the accumulation index (AI; ratio of AUC-day 5/AUC-day 1). Pharmacodynamic parameters were also measured over 24 h on day 1 and over 48 h on day 5: serum ACE activity and arterial blood pressure. RESULTS: Fosinoprilat pharmacokinetic parameters on day 1 in renally impaired vs normal patients: Cmax=387+/-0.19 vs 324+/-0.25 ng ml-1 (P=0.07); tmax=3.5 vs 3.0 h (P=0.58); AUC=3510+/-0.29 vs 2701+/-0.35 ng ml-1 h (P=0. 072); CUE=5.08+/-2.70 vs 7.40+/-2.56% (P=0.009). Fosinoprilat parameters on day 5: Cmax=517+/-0.40 vs 357+/-0.19 ng ml-1 (P=0. 007); tmax=3.0 vs 3.0 h (P >0.99); AUC=4098+/-0.43 vs 2872+/-0.30 ng ml-1 h (P=0.027); CUE=6.81+/-3.53 vs 8.10+/-2.80% (P=0.068). AI=1. 17+/-0.33 vs 1.06+/-0.23 (P=0.29). In both groups ACE inhibition and blood pressure response were similar over 24 h and slightly greater 48 h after last dosing. CONCLUSIONS: In renally impaired subjects fosinopril and HCTZ can be coadministered without undue increases in fosinoprilat concentrations or any clinically significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.     

Pharmacokinetics and tolerance of repeated oral doses of loxiglumide

The study was conducted on 6 adult healthy subjects (5 males and 1 female) in order to investigate the pharmacokinetics and tolerance of repeated b.i.d. oral administration for 7 days of tablets containing 400 mg of loxiglumide (CR 1505). The pharmacokinetics of loxiglumide in plasma after the first single dose of 400 mg is characterized by a lag time of 16 +/- 4 min, a rapid invasion (kinv = 10 h-1), a Cmax of 11.9 +/- 5.1 mg/l at tmax of 2.3 +/- 0.8 h, a mean residence time (MRT) of 6.9 +/- 1.1 h and an AUC of 60.6 +/- 16.3 (mg/l) x h. After the last dose of 400 mg the lag time was 17 +/- 6 min, the Cmax 12.7 +/- 3.8 mg/l at tmax of 2.1 +/- 0.8 h, a MRT of 11.0 +/- 1.9 h and an AUC of 109.8 +/- 39.9 (mg/l) x h. The increases of the AUC and of MRT were statistically significant and are probably due to an accumulation of loxiglumide which occurs during the repeated dose course and reaches the steady state within 48 h of repeated administration. Due to this accumulation the Cmax increased by 7%. The increase was not statistically significant or clinically relevant. No dose adjustment seems required during a repeated dose dosing schedule with 400 mg b.i.d. In the urine loxiglumide and 3 metabolites were found, which were called Metabolite (Met.) 11.2, Met. 12.0 and Met. 12.8. Met. 12.0 was the most abundant, accounting for 45% of the loxiglumide related substances excreted in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absence of food effect on the pharmacokinetics of telbivudine following oral administration in healthy subjects

The influence of food on the pharmacokinetics of telbivudine, a candidate antiviral agent against hepatitis B virus (HBV), was investigated in healthy adult subjects following a 600-mg oral dose administered with and without a high-fat/high-calorie meal. Telbivudine was well tolerated under fasting and fed conditions. Oral absorption of telbivudine as measured by maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and area under the plasma concentration-time curve (AUC(0-t) and AUC(0-infinity)) was not altered by food intake immediately before oral dosing. Values of Cmax, Tmax, and AUC were comparable when telbivudine was administered under fed and fasting conditions. Results from this study indicated that the absorption of telbivudine was not affected by a high-fat/high-calorie meal; telbivudine can therefore be administered orally with no regard to the timing of meals.     

Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p38 mitogen-activated protein kinase inhibitor: a first-in-human study

The objective of this study was to investigate the pharmacokinetics and ex vivo pharmacodynamics of increasing doses of RWJ 67657, along with the effect of food at one dose level in a first-in-human (FIH) study. This was a placebo-controlled, double-blind, randomized trial in healthy male subjects. Subjects received increasing doses of RWJ 67657 or placebo as a single oral dose (0.25-30 mg/kg) under fasting conditions. The effect of food was investigated for the 10-mg/kg dose. Plasma concentrations of RWJ 67657 were measured over a period of 48 hours using a validated LC-MS/MS method. To evaluate the pharmacodynamics of RWJ 67657, inhibition of cytokine production was monitored from exvivo-stimulated polymorphonuclear blood cells (PBMCs). Pharmacokinetic/pharmacodynamic modeling was used to characterize the inhibitory activity of RWJ 67657. RWJ 67657 was rapidly absorbed (mean tmax = 0.6-2.5 h). The pharmacokinetics of RWJ 67657 appear to be nonlinear with respect to single-dose administration of the investigative formulation. Coadministration of food did not have a significant effect on half-life or time to peak concentration (tmax) but decreased the exposure. Mean Cmax values in the presence of food were almost 50% lower than during fasting (542 vs. 1283 ng/mL), and the AUC decreased from 2832 to 1904 ng.h/mL with food. RWJ 67657 inhibited TNF-alpha, IL-8, and IL-6 in a concentration-dependent manner with mean IC50 values of 0.18 microM, 0.04 microM, and 0.43 microM, respectively. At 20 mg/kg, the median inhibition was greater than 85%. There were no significant adverse effects associated with single doses of this drug. This study demonstrates that RWJ 67657 has acceptable safety and pharmacokinetics to warrant further investigation in a repeat-dose setting. In addition, the early determination of effect on biomarkers suggests potential efficacy in diseases mediated by proinflammatory and inflammatory cytokines.     

Investigation of pharmacokinetic data of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin revealed from single and multiple oral dose studies with a hypericum extract containing tablet in healthy male volunteers

Hypericins, hyperforin and flavonoids are discussed as the main components contributing to the antidepressant action of St. John's wort (Hypericum perforatum). Therefore, the objective of the two open phase I clinical trials was to obtain pharmacokinetic data of these constituents from a hypericum extract containing tablet: hypericin, pseudohypericin, hyperforin, the flavonoid aglycone quercetin, and its methylated form isorhamnetin. Each trial included 18 healthy male volunteers who received the test preparation, containing 900 mg dry extract of St John's wort (STW 3-VI, Laif 900), either as a single oral dose or as a multiple once daily dose over a period of 14 days. Concentration/time curves were determined for the five constituents, for 48 h after single dosing and for 24 h on day 14 at the end of 2 weeks of continuous daily dosing. After single dose intake, the key pharmacokinetic parameters were determined as follows: Hypericin: Area under the curve (AUC(0-infinity)) = 78.33 h x ng/ml, maximum plasma concentration (Cmax) = 3.8 ng/ml, time to reach Cmax (tmax) = 7.9 h, and elimination half-life (t1/2) = 18.71 h; pseudohypericin: AUC(0-infinity) = 97.28 h x ng/ml, Cmax = 10.2 ng/ml, tmax = 2.7 h, t1/2 = 17.19 h; hyperforin: AUC(0-infinity) = 1550.4 h x ng/ml, Cmax = 122.0 ng/ml, tmax = 4.5 h, t1/2 = 17.47 h. Quercetin and isorhamnetin showed two peaks of maximum plasma concentration separated by about 3-3.5 h. Quercetin: AUC(0-infinity) = 417.38 h x ng/ml, Cmax (1) = 89.5 ng/ml, tmax (1) = 1.0 h, Cma (2) = 79.1 ng/ml, tmax (2) = 4.4 h, t1/2 = 2.6 h; isorhamnetin: AUC(0-infinity) = 155.72 h x ng/ml, Cmax (1) = 12.5 ng/ml, tmax (1) = 1.4 h, Cmax (2) = 14.6 ng/ml, tmax (2) = 4.5 h, t1/2 = 5.61 h. Under steady state conditions reached during multiple dose administration similar results were obtained. Further pharmacokinetic characteristics calculated from the obtained data were the mean residence time (MRT), the lag-time, the peak-trough fluctuation (PTF), the lowest observed plasma concentration (Cmin), and the average plasma concentration (Cav). The data obtained for the five consitituents generally corresponded well with values previously published. The trial preparation was well tolerated.     

The effect of food or sucralfate on the bioavailability of S(+) and R(-) enantiomers of ibuprofen.

This randomized, multiple cross-over pharmacokinetic study was undertaken to determine if food or sucralfate alter the bioavailability of the active S(+) enantiomer of ibuprofen. Eleven healthy adult male volunteers were given three single 600-mg doses of ibuprofen (separated by 1 week) administered either in a fasting state, after a standardized breakfast, or with sucralfate 1 g. The main outcome measures were area under the concentration (AUC), maximum peak plasma concentration (Cmax), and time to reach peak concentration (tmax) for total, S(+), and R(-) enantiomer serum ibuprofen levels, drawn up to 10 hours after dosing. The AUC for R(-) ibuprofen was significantly lower than S(+) ibuprofen in all three treatment groups. The treatments had no different effects on AUC for S(+), R(+), or total ibuprofen. There was no difference in the ratio of S(+):R(-) enantiomers across different treatment groups, but the intersubject variability was significant (P < .05). The S(+) ibuprofen Cmax was greater than the R(-) ibuprofen Cmax for all treatment groups (P < .05). Sucralfate reduced the peak concentration of both S(+) and R(-) enantiomers when compared with fasting (P < .05). There was a slight but nonsignificant increase in the mean time to achieve peak concentration of both S(+) and R(-) enantiomers. Neither food nor sucralfate has a significant effect on ibuprofen enantiomer pharmacokinetics, but interindividual variability contributes significantly to the variability of enantiomer bioavailability.     

Pharmacokinetics of eltoprazine in the dog

Pharmacokinetics of eltoprazine in male and female beagle dogs was studied in two separate cross-over experiments after administration of different intravenous and oral doses. After intravenous administration of 0.5 mg.kg-1, the mean volume of distribution was 5.7 +/- 1.1 l.kg-1. Clearance was 25.5 +/- 1.4 ml.min-1.kg-1. About 25% of the doses was excreted in urine, resulting ina renal clearance of 6.1 +/- 1.4 ml.min-1.kg-1. The mean elimination half-life (t1/2) after intravenous dosing was about 2.6 h. After oral dosing the plasma peak levels (Cmax) were proportional with the dose. The mean time to reach Cmax (tmax) varied between 1.5 and 1.9 h, and t1/2 was about 2.4 h, which was not significantly different (p greater than 0.05) from the half-life obtained after intravenous dosing. Plasma pharmacokinetics after single and multiple dosing of 4 mg.kg-1 showed no difference. Absolute bioavailability was 67% +/- 20%.     

Effects of Food on the Pharmacokinetics of Methylphenidate

Purpose. To test the hypothesis that the pharmacokinetics of d-meth- ylphenidate (d-MPH) would be altered by food ingested before administration of an immediate release formulation (dl-MPH- IR) but not when food is ingested before a slow release formulation (dl-MPH-SR). Methods. A randomized, four-phase, open label, crossover design was conducted in 24 healthy men who each received, on separate occasions, dl-MPH-IR and dl-MPH-SR taken after an overnight fast and 15 min after a standardized breakfast (20% protein, 21% fat, 59% carbohydrate). Plasma MPH levels were monitored by a validated, stereoselective, GLC-ECD method. Results. For plasma d-MPH, there were significant differences (ANOVA) between dl-MPH-IR and dl-MPH-SR in tmax, Cmax (peak exposure), and Cmax/AUC (sensitive to rate of absorption). Dl-MPH-SR on average delayed tmax from 2.3 to 3.7 h and lowered Cmax 34%. There was no significant difference between the formulations in AUC (extent of absorption). For dl-MPH-IR, food significantly increased Cmax (23%) and AUC (15%) and for dl-MPH-SR the corresponding increases were Cmax (17%) and AUC (14%). After dl-MPH-IR, food delayed average tmax from 2.0 to 2.5 but had no effect on tmax after dl-MPH-SR. There was no effect of food on Cmax/AUC (rate of absorption). Conclusions. Food caused a significant increase in extent of absorption but had no effect on rate of absorption of d-MPH after either dl-MPHIR or dl-MPH-SR.     

Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation

The effect of food on the relative bioavailability of an erythromycin particles-in-tablet formulation was studied in 27 healthy volunteers, using a four-way, crossover study design with the following treatments: one or two erythromycin capsules USP (Eryc, Parke-Davis), or one polymer-coated erythromycin particles-in-tablet (PCE, Abbott) administered fasting or with a high-fat meal. Under fasting conditions the erythromycin particles-in-tablet and erythromycin capsule formulations are bioequivalent based on similar tmax and dose-normalized Cmax and AUC values. The rate and extent of absorption from the particles-in-tablet formulation, however, are dramatically reduced following administration with a meal. Mean Cmax and AUC values decreased by 73% and 72%, respectively, and seven subjects had no detectable erythromycin plasma concentrations for 16 hours following administration of the particles-in-tablet formulation with the high-fat meal. Greater than 40% of the subjects had nonfasting Cmax and AUC values that were less than 10% of those values following administration of the dose fasting. Cmax and AUC values in nonfasting subjects were within 75% to 125% of fasting values in only two and one of 27 subjects, respectively. The erythromycin particles-in-tablet formulation therefore should not be administered with meals.     

Absence of effect of food on alprazolam absorption from sustained release tablets

This study examined the effect of food on alprazolam absorption from a mixed polymeric matrix sustained release (SR) tablet in 21 healthy adults. Each subject received each of three treatments according to a crossover design: 1 mg alprazolam SR tablet while fasting; 1 mg alprazolam SR tablet immediately after a standardized breakfast; 1 mg alprazolam conventional tablet while fasting. The breakfast contained approximately 33 g protein, 55 g fat, and 58 g carbohydrate (850 calories). Serial blood samples were obtained and plasma alprazolam levels determined by HPLC. Results indicate that the SR tablet was minimally affected by food. Relative bioavailabilities of the SR tablet while fasting and with food were 100 per cent and 97 per cent, respectively. Although statistically significant, differences in mean Cmax values between SR tablets administered with and without food were small (12 per cent increase with food). Rates of absorption as measured by mean tmax values were also nearly the same: 7.2 h while fasting and 7.0 h with food. Absorption was relatively uniform with the SR tablets. Coefficients of variation for Cmax, tmax, and AUC were somewhat smaller with the SR tablet than with the conventional tablet.     

替硝唑片在回族和汉族健康人体的药动学研究

目的:研究回族和汉族健康志愿者单剂量口服替硝唑片的药动学。方法:健康志愿者20名(回族、汉族各10名,男女各半)单剂量口服替硝唑片1g,采用高效液相色谱法测定血浆中替硝唑的含量。用DAS程序软件进行数据处理并采用SPSS软件进行统计学分析。结果:回族、汉族受试者单剂量口服替硝唑片1g的主要药动学参数:Cmax分别为(20.25±4.05)、(19.04±2.42)μg·mL-1,tmax分别为(2.10±0.66)、(2.15±0.47)h,t1/2分别为(16.81±1.56)、(16.94±2.40)h,AUC0～72分别为(483.51±116.83)、(454.37±59.74)mg.h.L-1,AUC0～∞分别为(514.25±130.78)、(486.14±65.63)mg.h.L-1。男、女受试者的主要药动学参数:Cmax分别为(17.16±1.28)、(22.12±2.79)μg·mL-1,tmax分别为(2.20±0.59)、(2.05±0.55)h,t1/2分别为(17.32±1.97)、(16.43±1.97)h,AUC0～72分别为(406.83±44.40)、(531.05±84.54)mg.h.L-1,AUC0～∞分别为(437.11±54.73)、(563.27±100.06)mg.h.L-1。结论:替硝唑片在回族和汉族健康志愿者体内药动学参数不存在种族差异,但存在性别差异。     

Effect of high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of vardenafil,an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction

The effects of food on the pharmacokinetics of vardenafil were examined in 25 healthy adult males. Single-dose vardenafil 20 mg was administered in a randomized four-way crossover design after an overnight fast (at 8 a.m.), after consumption of a high-fat breakfast (at 8 a.m.), on an empty stomach (at 6 p.m.), and after a typical moderate-fat evening meal (at 6 p.m.). Serial blood samples were analyzed for vardenafil and metabolite (M1) levels. When administered after an overnight fast and after a high-fat breakfast, vardenafil geometric mean Cmax was 17.14 and 14.0 micrograms/L, respectively, and AUC was 66.78 and 67.09 micrograms./h/L, respectively; the median tmax was 1 hour under fasting conditions and 2 hours with consumption of high-fat breakfast. When administered in the evening on an empty stomach and after a moderate-fat meal, vardenafil geometric mean Cmax was 14.22 and 13.04 micrograms/L, respectively, and AUC was 51.97 and 59.12 micrograms.h/L, respectively. The median tmax was 1 hour after fasting or a moderate-fat meal in the evening. All treatments were well tolerated. Thus, while a high-fat meal may alter Cmax slightly and delay the absorption up to 1 hour, a moderate-fat meal has no clinically relevant effect on vardenafil pharmacokinetics. Dosage changes are not warranted based on the wide therapeutic index and the efficacy observed with vardenafil in Phase III studies that were not restricted with respect to food.     

Gastrointestinal behavior of orally administered radiolabeled erythromycin pellets in man as determined by gamma scintigraphy

The behavior of single 250-mg doses of a multiparticulate form of erythromycin base (ERYC(R)), each including five pellets radiolabeled with neutron-activated samarium-153, was observed by gamma scintigraphy in seven male subjects under fasting and nonfasting conditions. The residence time and locus of radiolabeled pellets within regions of the gastrointestinal tract were determined and were correlated with plasma concentrations of erythromycin at coincident time points. Administration of food 30 minutes postdosing reduced fasting plasma erythromycin Cmax and area under the plasma erythromycin versus time curve (AUC) values by 43% and 54%, respectively. Mean peak plasma concentration of erythromycin (Cmax) in the fasting state was 1.64 micrograms/mL versus 0.94 micrograms/mL in the nonfasting state. Total oral bioavailability, as determined by mean AUC (0-infinity) of the plasma erythromycin concentration versus time curve, was 7.6 hr/micrograms/mL in the fasted state, versus 3.5 hr/micrograms/mL in the nonfasting state. Mean time to peak plasma erythromycin concentration (tmax) in the fasting state was 3.3 hours, versus 2.3 hours in the nonfasting state. Plasma concentrations of erythromycin in both fasting and nonfasting states were within acceptable therapeutic ranges. Evidence provided by this study: 1) indicates that pellet erosion and absorption of active erythromycin base begins when the enteric-coated pellets reach the highly vascular mucosa of the jejunum and proximal ileum, and is essentially completed within the ileum, with a significant portion absorbed in the medial-to-distal ileum; 2) confirms that acceptable therapeutic plasma levels of erythromycin are attained in nonfasting subjects (Cmax = 0.94 microgram/mL) and that superior plasma erythromycin concentrations (Cmax = 1.64 micrograms/mL) are achieved by administration of the dose on an empty stomach 1 to 2 hours before or after meals; 3) corroborates other comparative studies reporting greater fasting bioavailability with this multiparticulate dosage form of erythromycin base than with reference single tablet or particle-in-tablet formulations; and 4) indicates that neutron activation of stable isotopes incorporated as a normal excipient in industrially-produced formulations provides an effective means for in vivo evaluation of dosage forms through gamma scintigraphy.