Methaqualone pharmacokinetics after single- and multiple-dose administration in man

Serum levels of methaqualone (MTQ) were determined in eight unfasted subjects following single- and multiple-dose administration of 1×300 mgtablet over a 28-day period. Data were analyzed by a two-compartment open model. Following a fairly rapid absorptive phase (K _a =0.82±0.32 hr^–1),the serum elimination curve was biexponential, consisting of a phase predominantly due to distribution (=0.97±0.55 hr^–1)and a phase predominantly due to elimination (=0.036±0.004 hr^–1).A steady-state MTQ serum concentration profile was observed within the first week. There were no significant changes in the kinetics of absorption, distribution, or elimination over the 28-day period of drug administration. Urinary D-glucaric acid excretion, which increased two-to threefold after the first week of MTQ dosing, returned to normal levels when the drug was discontinued. The significance of the pharmacokinetic parameters in relation to bioavailability and biological disposition of single and multiple dose MTQ administration is discussed.     

Pharmacokinetic and tolerance studies of cefpodoxime after single- and multiple-dose oral administration of cefpodoxime proxetil.

Cefpodoxime proxetil, a third generation, broad-spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of cefpodoxime proxetil were determined. Results from the single-dose study indicate that cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose-normalized AUC and Cmax, urinary recovery, and half-life between one or more of the higher-dose treatment groups and the 100-mg dosing group. After multiple-dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single-dose study and antibiotic-associated diarrhea in one subject in the multiple-dose study.     

Topical skin penetration of diclofenac after single- and multiple-dose application

OBJECTIVE: Transdermal penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to be highly variable. The present study was performed to gain insight into the transdermal penetration process of topically applied diclofenac and to test whether transdermal absorption leads to pharmacologically effective concentrations in dermal tissue layers beneath the application site. MATERIAL AND METHOD: Six healthy male volunteers participated in this 2-way crossover study and were assigned to 2 treatment groups. In the first group, diclofenac was applied at a therapeutic dose of 60 mg/100 cm2 3 times daily for 4 days with subsequent occlusion with a plastic foil for 4 hours to enhance transdermal drug absorption. After a 1-week wash-out, diclofenac was applied at a single dose of 300 mg/100 cm2 without occlusion. Diclofenac in both groups was applied on a previously shaven area of the thigh. Transdermal penetration was assessed employing in vivo microdialysis. RESULTS: After multiple-dose administration mean diclofenac concentrations of 0.48 +/- 0.35 ng x ml(-1) were observed in subcutaneous tissue (mean +/- SEM). The mean AUC(subcutis/plasma) ratio of 0.08 +/- 0.02 indicates redistribution of diclofenac from the systemic circulation to the tissue. After single-dose treatment, mean tissue concentrations were 24.26 +/- 46.43 ng x ml(-1) with a mean AUC(subcutis/plasma) ratio of 60.85 +/- 57.59, which suggests direct tissue penetration of diclofenac. CONCLUSIONS: Transdermal penetration of diclofenac after multiple as well as after single application of the present formulation is highly variable. In addition to other factors influencing the transdermal penetration process, dose and mode of administration are important factors determining whether pharmacologically effective local tissue concentrations are attained.     

Simultaneous modelling of mexiletine and hydroxy-methyl-mexiletine data after single- and multiple-dose administration of a sustained-release mexiletine formulation.

The pharmacokinetics of mexiletine and its metabolite hydroxy-methyl-mexiletine have been investigated following single-dose and during multiple-dose administration of a sustained-release form of mexiletine to six post-myocardial infarct patients. Comparison of single-dose and washout pharmacokinetics, after short-term multiple-dose administration, showed significant (p < 0.005), but not systematic, modifications in mexiletine apparent clearance for three patients. Furthermore, for these patients, simulation with both sets of parameters indicated that the steady-state was achieved before washout experiment in two cases. The fraction of mexiletine metabolized to hydroxy-methyl-mexiletine was lower for multiple-dose administration (about 18 per cent) than for the single dose (about 42 per cent). The hydroxy-methyl-mexiletine elimination rate constant was about four times that of mexiletine. Mexiletine clearance could be accounted for by other metabolic pathways. In one patient, hydroxy-methyl-mexiletine was undetectable even during multiple-dose administration, despite a significant increase in mexiletine clearance. However, the observed changes in mexiletine disposition had no therapeutic implications and active plasma levels were achieved by the third day of administration and maintained in the therapeutic range (0.75 to 2 micrograms ml-1) in all patients after a twice daily dosage regimen.     

Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple-dose administration in healthy older adults

The pharmacokinetics of exogenously administered DHEA have not been well characterized despite its increasing use in therapeutic and research investigations. The purpose of this study was to evaluate the pharmacokinetics of DHEA and its sulfated metabolite (DHEA-S) after single- and multiple-dose oral administration of DHEA 200 mg. Healthy older adult volunteers (7 women, 6 men) ages 65 to 79 years were studied on five visits separated by 1 week. Subjects received daily administration of placebo (days 1 to 7), DHEA 200 mg (days 8 to 22), and placebo (days 23 to 29). Blood samples were collected over 24 hours on days 1, 8, 15, 22, and 29 for DHEA and DHEA-S determinations by RIA. Pharmacokinetic parameter estimates were calculated by noncompartmental methods. Administration of DHEA 200 mg resulted in higher DHEA Cmax, AUC, and overall concentrations in women than in men (p < 0.03); DHEA-S parameter estimates were similar between men and women. Following a single dose of DHEA 200 mg, DHEA concentrations increased 5- to 6-fold in both men and women, and DHEA-S concentrations increased 5-fold in men and 21-fold in women relative to endogenous concentrations. The results of this study indicate that the pharmacokinetics of DHEA differ between older men and women.     

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration to administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively, these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution.     

Pharmacokinetics of dolasetron following single- and multiple-dose intravenous administration to normal male subjects

Dolasetron, Anzemet^TM, a 5-hydroxytryptamine receptor antagonist, is under investigation as an antiemetic agent. The keto-reduced metabolite of dolasetron has been identified in human plasma and is probably responsible for the majority of the antiemetic activity. This study evaluated the pharmacokinetics of dolasetron and the reduced metabolite following single and multiple intravenous (IV) infusions of dolasetron mesylate in healthy male subjects. Four groups of subjects (six active/two placebo) received either dolasetron mesylate or placebo in single IV doses ranging from 0.30 to 0.60 mg kg^?1 on day 1 and multiple IV doses ranging from 0.60 to 1.20 mg kg^?1 d^?1 on days 2–9. Dolasetron could be detected for less than 1 h, while the reduced metabolite appeared rapidly in the plasma, reaching a maximal plasma concentration in less than 1 h. Reduced metabolite maximal plasma concentration was proportional to the dose and the area under plasma concentration curve was linear based on regression analysis. The half-life of reduced metabolite ranged from 3.82 to 7.46 h. The mean renal clearance of reduced metabolite was 2.20–4.43 mL min^?1 kg^?1 and was dose independent. All of the evidence supports dose independent pharmacokinetics for the reduced metabolite. Upon multiple dosing, the reduced metabolite AUC can be predicted from the single-dose pharmacokinetics of this metabolite.     

Kinetics of acetaminophen after single- and multiple-dose oral administration as a gradient matrix system to healthy male subjects

The in vivo characteristics of two formulations of a recently developed controlled-release system, the Gradient Matrix System (GMS-1 and GMS-2), with acetaminophen as a model drug compound have been determined in healthy volunteers both after separate single- and multiple-dose administration. Values for the mean residence time (MRT) were increased from 5.2 h for an oral solution to 10.2 and 13.3 h for two GMS formulations after single dosing. Peak plasma concentrations were lower for the two GMS formulations after single dosing compared to the oral solution. The bioavailability, relative to the oral solution, was 91 per cent and 84 per cent for the two GMS formulations tested. After multiple dosing of one of the GMS formulations over 5 days, no change in AUC compared to the single dose AUC occurred. Steady state was reached within 2-3 days of twice daily dosing of the GMS formulation. The peak-trough-fluctuation (per cent PTF) was 44 per cent. No signs of dose dumping were observed in fasted subjects. A plateau-like plasma drug concentration profile at steady state was maintained with the GMS formulation.     

Use of metoclopramide, domperidone, and cisapride in the management of diabetic gastroparesis

The pathophysiology, diagnosis, and treatment of diabetic gastroparesis are reviewed, and the mechanisms of action, pharmacokinetics, clinical efficacy, adverse effects, and dosage of metoclopramide, domperidone, and cisapride are described. Diabetic gastroparesis is a state of delayed gastric emptying that reportedly affects 20-30% of diabetic patients. Symptoms include nausea, early satiety, postprandial bloating and fullness, and vomiting. Diabetic gastroparesis has been managed most successfully with drugs that stimulate gastric emptying. Of the three agents studied--metoclopramide, domperidone, and cisapride--only metoclopramide is commercially available in the United States. The clinical efficacy of metoclopramide, domperidone, and cisapride has been well documented in several placebo-controlled trials. Metoclopramide effectively decreases mean gastric emptying time, although tolerance to this stimulation of gastric emptying may develop with long-term therapy. However, symptomatic relief persists with long-term therapy because of metoclopramide's antiemetic properties. Domperidone, which has also been shown to stimulate gastric motility and to possess antiemetic properties, improves symptoms in patients suffering from diabetic gastroparesis. Cisapride appears to have continued beneficial effects on gastric motility with long-term therapy. All three agents have favorable adverse-effect profiles. Although metoclopramide is currently the first-line agent for the management of gastroparesis, domperidone and cisapride both possess properties that may make them useful alternatives in patients who are unresponsive to or cannot tolerate metoclopramide therapy.     

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects.

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively; these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution.     

糖尿病胃轻瘫患者异常胃肌电活动的观察与分析

目的通过胃电图检查研究糖尿病胃轻瘫患者异常胃肌电活动，探讨胃动力异常在糖尿病胃轻瘫发生中的作用。方法67例糖尿病胃轻瘫患者行餐前和餐后体表胃电图检查，对正常胃慢波百分比和胃电主功率两项参数进行分析。结果本组糖尿病性轻瘫患者中胃电节律正常占41．8％、胃动过缓占32．8％、胃动过速占7．5％和混合性胃电节律紊乱占17．9％。在胃电节律正常的糖尿病胃轻瘫患者中，10例（35．7％）存在餐后／餐前胃电主功率比异常。结论胃动力异常在糖尿病胃轻瘫发病机制中起有重要作用。     

Pharmacokinetics of PC-SOD, a lecithinized recombinant superoxide dismutase, after single- and multiple-dose administration to healthy Japanese and Caucasian volunteers

To study the pharmacokinetics of single increasing intravenous doses (40-160 mg) and repeated doses (80 mg for 7 days) of lecithinized superoxide dismutase (PC-SOD) in Japanese volunteers and to compare the pharmacokinetics of PC-SOD between Caucasians and Japanese. The Japanese study consisted of 2 parts: a single-dose, open-label, dose-escalation part and a multiple-dose, single-blind, placebo-controlled part. The pharmacokinetics of PC-SOD were determined using noncompartmental and compartmental methods. Pharmacokinetic data from a study with PC-SOD in Caucasians were reanalyzed using the same methodology. The mean (SD) terminal half-life of PC-SOD in Japanese subjects was 25 (4) hours for the 40-mg and 80-mg doses and 31 (15) hours for the 160-mg dose. There was nonlinearity between dose-normalized C(max) and clearance (P values .002 and .022). After multiple dosing, steady state was reached after 5 days. The observed accumulation ratio was 2.6 (0.5). The pharmacokinetics of the single 80-mg dose were similar for Japanese and Caucasians. The pharmacokinetics of PC-SOD was shown to be nonlinear with dose, which may be attributable to a saturable clearing mechanism. The relatively long half-life of PC-SOD (>24 hours) suggests that it is worthwhile to study the compound as a protective agent in clinical conditions with free radical overload.     

Bioavailability of dexmedetomidine after intranasal administration

Purpose  

The aim of this proof-of-concept study was to characterize the pharmacokinetics and pharmacodynamics of intranasal dexmedetomidine compared with its intravenous administration in a small number of healthy volunteers.     

复方阿嗪米特对糖尿病性胃轻瘫患者的治疗效果分析

目的观察复方阿嗪米特肠溶片联合莫沙比利对糖尿病性胃轻瘫的疗效。方法分60例糖尿病性胃轻瘫患者为2组,实验组予复方阿嗪米特肠溶片联合莫沙比利、对照组予莫沙必利治疗,比较两组疗效。结果治疗2周和4周后,实验组患者症状评分明显低于对照组（P〉0．05）。治疗4周后实验组胃排空时间（166．33±65．21）min明显短于对照组（204．24±73．41）min,两组比较差异统计学意义（t=2．11,P〈0．05）。结论复方阿嗪米特联合莫沙比利用于糖尿病性胃轻瘫的治疗,可有效缓解患者的胃肠道症状,减少患者胃排空时间。     

Naltrexone disposition in man after subcutaneous administration

The metabolism, excretion, and pharmacokinetics of [15,16-3H2]naltrexone were studied in six human males after sc administration of the hydrochloride salt. Biological fluids were analyzed by a combination of high performance liquid chromatography with liquid scintillation measurement of radioactivity. After administration, naltrexone was rapidly absorbed into the systemic circulation. The mean absorption rate constant was 0.091 +/- 0.008 min-1 (half-life of 7.6 min). In general the metabolic, excretory, and pharmacokinetic patterns for naltrexone were similar to those observed after iv administration of naltrexone to man. The terminal phase plasma rate constant was 0.413 +/- 0.035 hr-1 (half-life of 1.68 hr) for parent drug and 0.0786 +/- 0.0090 hr-1 (half-life of 8.8 hr) for the major metabolite, 6 beta-naltrexone. An average of 76 +/- 6% (+/- SD) of the total radioactivity was recovered in the urine within 72 hr after administration. Naltrexone was found in the urine in both the free (3.4 +/- 0.8% of dose) and conjugated (6.8 +/- 2.1% of dose) form. 6 beta-Naltrexol was present in urine largely in the unconjugated form (28 +/- 7% of dose) but the conjugated form was also found (12 +/- 3% of dose).     

Bioavailability of metoclopramide in a sustained-release preparation

The aim of this study was to examine the pharmacokinetical behaviour of metoclopramide of Gastronetron retard capsules after a single administration to 8 healthy male volunteers. Determinations of the concentration of metoclopramide in the serum were made up to 24 h p.a. The calculation of the serum concentration curves was based on an open 2-compartment model. It has been proved that already 30 min after oral administration effective serum concentrations could be reached, which are maintained over about 24 h. An approximate value of 71% was obtained for the bioavailability of metoclopramide of Gastronerton retard capsules. The action achieved by the administration of 1 capsule Gastronerton retard per day can be considered equal to that of 3 single administrations of the conventional oral pharmaceutical form.     

Bioavailability and pharmacokinetics of rectally administered metoclopramide

The absolute and relative bioavailability of metoclopramide following the administration of a single suppository--test (Gastrosil) and reference preparations--containing 20 mg of the pure drug or after i.v. injection of 17.8 mg was compared in 12 sex matched healthy volunteers according to an open, three-way cross-over, intra-individual design. The metoclopramide plasma levels were determined up to 32 h following rectal administration and 24 h following intravenous application using a modified and specific HPLC-assay. The areas under the concentration-time curves were either calculated to the last time-interval measured (AUC-1) by using the trapezoidal rule or by extrapolating to infinity (AUC(0-infinity] in a model-dependent manner. Pair-differences and ratios were taken for the individual AUC-values and for the maximum plasma levels (cmax-values) at the corresponding time values (tmax-values) for test and reference formulations and tested for statistical significance. The results showed the mean AUC-1 and AUC (0-infinity)-values respectively to be 10.7% and 9.5% lower for the test suppository. The mean tmax-values were found to be 21% and 11.6% lower and the mean cmax-values were found to be about 4.3% larger than the corresponding parameters for the reference formulation. The 95% Wilcoxon confidence limits for both test and reference preparation were found to range from 80.2-108.9% for all AUC-values and to lie in the region 83.5-120.3% and 57.8-100% for the cmax- and tmax-values, respectively. Thus, with respect to the pharmacokinetic target parameters, little difference can be found between the two suppository forms each containing 20 mg metoclopramide-base and under trial in this study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of age on single- and multiple-dose pharmacokinetics of erythromycin

Summary The activity of the substituted benzamide renzapride on the upper gastrointestinal tract has been investigated. It has been shown to enhance stomach emptying in normal subjects; doses of 2 and 5 mg decreasing by 21 and 37% respectively the volume of gastric contents aspirated 80 min after a test meal. Renzapride was found to reduce the oro-caecal transit time as assessed by the lactulose/breath hydrogen method in a dose related manner from 0.2 to 5 mg; the later dose producing a 62% reduction. Finally renzapride was shown not to elevate plasma prolactin at a dose of 5 mg, a finding consistent with lack of dopamine receptor antagonism.