Oxaprozin pharmacokinetics in patients with congestive heart failure

12 patients aged 26-71 years with stable, compensated congestive heart failure (CHF) and 12 healthy controls matched for age, sex, height, weight, and serum albumin, received a 1200-mg oral dose of the nonsteroidal antiinflammatory agent 4,5-diphenyl-2-oxazolepropionic acid (oxaprozin). Serum oxaprozin levels were measured by high pressure liquid chromatography during the next 14 days. Oxaprozin elimination half-life was not different between controls and CHF patients (63 vs 69 h), but peak serum levels were lower (79 vs 63 micrograms/ml, p less than 0.01), apparent volume of distribution was larger (0.22 vs 0.29 l/kg, p less than 0.05) and clearance tended to be higher, although not significantly so, (0.042 vs 0.053 ml/min/kg) in CHF patients. These differences might have been due to reduced serum protein binding (increased free fraction) in CHF patients (0.25 vs 0.44% unbound, p less than 0.1). After correction for individual values of free fraction, groups did not differ in peak free oxaprozin serum levels (0.20 vs 0.26 micrograms/ml), unbound volume of distribution (92 vs 83 l/kg), or unbound clearance (17.5 vs 15.0 ml/min/kg). Thus protein binding of oxaprozin in the present study was reduced in CHF due either to the underlying disease or to the concurrent medications. This in turn caused reciprocal reduction in total (free plus bound) oxaprozin levels and elevated estimates of volume of distribution and clearance. Although protein binding is altered, CHF causes no significant alteration in distribution of free oxaprozin nor free clearance of oxaprozin, which is accomplished by a combination of oxidation and conjugation.     

Cyclosporin pharmacokinetics in the elderly.

Cyclosporin is an immunosuppressant used in organ transplantation and selected autoimmune diseases such as rheumatoid arthritis. In both these indications, the elderly represent an important and growing segment of the patient population. Cyclosporin is primarily eliminated via biotransformation by cytochrome P450 (CYP)3A in the gut wall and liver. Additionally, P-glycoprotein (mdr-1) located in the gastrointestinal epithelium can affect affect blood drug concentrations after oral administration of cyclosporin, presumably by counter-transporting the drug from the systemic circulation back into the gastrointestinal lumen. Theoretically, age-related alterations in either of these pathways could affect cyclosporin disposition in the elderly. These general pharmacological considerations together with the narrow therapeutic index of cyclosporin between minimally immunosuppressive concentrations and those associated with adverse events, underscore the need for dedicated pharmacokinetic studies in the elderly. Single dose studies have demonstrated that cyclosporin pharmacokinetics are not different in healthy elderly individuals compared with healthy young adults, nor is the between-subject variability in pharmacokinetic parameters more heterogenous in healthy elderly individuals. Similarly, there were no apparent differences in cyclosporin disposition in elderly patients with rheumatoid arthritis compared with healthy young and elderly individuals. Whether pharmacokinetic variability may be increased in elderly patients has not been rigorously addressed and requires investigation in a larger patient population for a definitive conclusion. A population pharmacokinetic study of cyclosporin in organ transplant patients, including elderly allograft recipients up to 75 years of age, did not identify age as a covariable influencing cyclosporin pharmacokinetics. Hence, the available pharmacokinetic data in the elderly do not reveal any major differences from the disposition characterised in younger individuals. It is generally recognised that the elderly are more prone to drug-related adverse experiences and are at greater risk for drug-drug interactions secondary to polypharmacy. The former factor may underlie, in part, the increased incidence of renal adverse events reported in patients with rheumatoid arthritis over 65 years of age receiving cyclosporin. Clinical experience with cyclosporin in elderly organ transplant recipients has not revealed a tolerability profile remarkably different from those in younger patients. Polypharmacy may have specific relevance for elderly patients treated with cyclosporin since this agent is a substrate of both CYP3A and P-glycoprotein, both of which are important in the elimination of many commonly used drugs. This implies that the clinician prescribing cyclosporin for an elderly patient must exercise a heightened awareness for potential drug-drug interactions which could affect the pharmacokinetics of cyclosporin. Based on the available cyclosporin pharmacokinetic data in adults, no age-related administration adaptations appear necessary for its use in the elderly.     

Naproxen pharmacokinetics in the elderly.

While naproxen pharmacokinetics appear to be altered in the presence of both diminished renal and hepatic function, the degree to which naproxen disposition might be influenced in the elderly by concurrent alteration in these functions is not obvious. Total plasma clearance/bioavailability (CL/F) of naproxen after a single 375 mg oral dose was found to be less in a group of 10 healthy men between 66 and 81 years of age than in 10 healthy men between 22 and 39 years (0.318 +/- 0.078, 0.416 +/- 0.061 l/h). At steady state (375 mg, 12 hourly), however, CL/F was statistically indistinguishable between the two groups. The fraction of naproxen unbound to plasma protein was doubled in elderly subjects, both at peak and trough drug concentrations. The lowered protein binding tended to obscure a 50% decrement in the intrinsic clearance of naproxen in the elderly as estimated by unbound clearance/bioavailability (213 +/- 64, 396 +/- 155 l/h). As a result, mean steady-state plasma concentrations of naproxen were indistinguishable between the elderly and young (64.2 +/- 8.5, 58.2 +/- 8.1 mg/l) but the elderly generated twice the mean steady-state unbound plasma drug concentration (0.157 +/- 0.039, 0.0859 +/- 0.0212 mg/l). Since it is the unbound drug concentration which appears in general to relate more closely to pharmacological and toxic effect, it may be advisable to reduce naproxen doses by half in the elderly, pending plasma drug concentration-response studies in this age group. If a similar perturbation with age occurs in benoxaprofen protein binding as was observed with naproxen, benoxaprofen intrinsic clearance in the elderly might be only one quarter of that in younger individuals; a factor which may contribute to the toxicity of this drug in the elderly.     

奥沙普秦肠溶胶囊与片在中国健康者的药物动力学及相对生物利用度

目的：了解国产奥沙普秦肠溶胶囊在人体的药物动力学及相对生物利用度。方法：采用随机交叉试验设计,１０例男性健康者单剂量口服奥沙普秦肠溶胶囊与片剂 ６００ ｍｇ,以 ＨＰＬＣ法测定血药浓度。结果：胶囊与片剂各项动力学参数为：（１）ＡＵＱＯ　——（７５７２±ｓ ６９５） ｍｇ· Ｌ－１与（８２０１± ９４９）ｍｇ．Ｌ－１．ｈ－１;（２）Ｔ １／２－（５９±７） ｈ与（５３±４ ） ｈ ,上述２参数经ｔ检验;差别无统计学意义（Ｐ＞０． ０５）;（３） Ｃｍａｘ－－（８３± １５）ｍｇ．Ｌ－１与（１２６± ２１）ｍｇ·Ｌ－１;（４） Ｔｍａｘ－（１５± ７） ｈ与（４± ３） ｈ,经方差分析,均 Ｐ＜ ０． ０５,符合肠溶制剂原有性质。胶囊的相对生物利用度为（９３± １３）％,经双向单侧 ｔ检验作统计学分析,（Ｐ＞０．０５）。结论：胶囊与片剂两者之间具有生物等效性。     

荧光分光光度法测定奥沙普嗪肠溶胶囊的含量

目的:建立奥沙普嗪肠溶胶囊的荧光测定法.方法:以无水乙醇为溶剂,采用荧光分光光度法测定奥沙普嗪肠溶胶囊的含量,测定波长为Ex=287.0nm,Em=368.0nm.结果:平均回收率99.71%,RSD为0.89%,线性范围为0.2～1.0μg·ml-1.结论:该方法简便、灵敏、准确,适用于奥沙普嗪肠溶胶囊的含量测定.     

The pharmacokinetics of doxazosin in elderly normotensives.

The pharmacokinetics of doxazosin were studied in 12 normotensive elderly volunteers aged 62-89 years. There was marked inter-individual variability in all the parameters derived but the disposition of doxazosin was similar in both sexes. These results were compared to those of a group of young normotensive volunteers aged 23-39 years studied previously under comparable conditions. The volume of distribution increased significantly with age although the bioavailability and clearance were not significantly different in the two groups. These results suggest that age is unlikely to influence the disposition of doxazosin to a clinically significant extent.     

反相高效液相色谱法测定奥沙普嗪分散片中奥沙普嗪含量

目的建立测定奥沙普嗪分散片中奥沙普嗪含量的高效液相色谱法。方法采用反相高效液相色谱法,以Hypersil C18柱(200 mm×4.6 mm,5μm)为色谱柱,以0.01 mol/L磷酸二氢钾溶液(磷酸调pH至2.5)-乙腈(40∶60)为流动相,检测波长为286 nm,流速为1.0 mL/min,柱温30℃。结果奥沙普嗪质量浓度在4.0～24.0μg/mL范围内与峰面积线性关系良好,高中低3种质量浓度的回收率为97.6%～101.3%,RSD为1.1%～1.8%。结论所建立的方法快速、准确、简便,适用于奥沙普嗪分散片的质量控制。     

Sorbinil pharmacokinetics in male and female elderly volunteers.

Sorbinil pharmacokinetics were studied, following a single oral dose, in eight male and eight female healthy, elderly volunteers. Elimination half-life tended to be longer in males than in females. There was no sex difference in AUC or renal clearance. The long elimination half-life of sorbinil in the elderly suggests that accumulation is likely to occur with chronic dosing.     

Flunoxaprofen pharmacokinetics in elderly subjects

Plasma kinetics and 24 h urinary elimination of flunoxaprofen, a nonsteroidal antiinflammatory drug, were studied in 23 elderly patients (mean age 69.9 years) and compared with the data obtained in four young volunteers. The drug was administered as a single oral 100 mg tablet and its plasma and urine concentrations were assayed by a high performance liquid chromatography method. Plasma kinetics fitted a 3-exponential equation with a mean half-life of 7.9 +/- 2.17 hours and a mean peak plasma of 8.5 +/- 2.97 micrograms/ml, which was observed at about the second hour. The values of the areas under the curves (AUC) and the values of total clearance (multiplied by the bioavailability) showed great variability, due to the large differences in the patients body weights; in fact the value of AUC was linearly correlated to the dose divided by the body weight. The mean residence time (MRT) of the drug in plasma was equal to 12.81 h. Low amounts of unmodified drug (about 10%) were found in 24 h urine sample, indicating a high degree of biotransformation. Small differences only were found in plasma kinetics of flunoxaprofen among the present group of elderly patients and the group of four young volunteers; the main difference corresponded to a slower rate of gastrointestinal absorption and to a longer mean residence time.     

Clarithromycin pharmacokinetics in healthy young and elderly volunteers.

The pharmacokinetics of clarithromycin and its active 14(R)-hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)-hydroxyclarithromycin concentrations were determined using high-performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration-time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 +/- 97 versus 476 +/- 112 mL/min, respectively) and renal clearance (CLR) (84 +/- 31 versus 168 +/- 35 mL/min, respectively). Similar results were noted for the 14(R)-hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.     

Vinpocetine pharmacokinetics in elderly subjects

The pharmacokinetics of vinpocetine (Eusenium) were investigated in 20 elderly, healthy volunteers. Plasma levels of the drug were determined during one dose interval of either repeated intravenous infusion or oral administration. AUC, Cmax and tmax values were derived for oral application, AUC values in case of intravenous application. Oral administration of 20 mg vinpocetine resulted in 4.60 x 10(-8) mol l-1 h, 1.71 x 10(-8) mol l-1 and 2.33 h for AUC, Cmax and tmax, respectively. The appropriate values for apovincaminic acid were 1.92 x 10(-6) mol l-1 h, 6.39 x 10(-7) mol l-1 and 2.41 h. When 10 mg vinpocetine were infused for 1 h, AUC values for vinpocetine and apovincaminic acid were 3.42 x 10(-7) mol l-1 h and 1.69 x 10(-6) mol l-1 h. Absolute bioavailability of vinpocetine was 6.7%. These data were in good agreement with the literature on young and elderly subjects. Marked deviations of apovincaminic acid kinetics in elderly subjects as described earlier could not be demonstrated in this study.     

噁丙嗪的合成

本文讨论了噁丙嗪合成条件的优化设计,产品的纯制方法及钙盐的制备方法.     

Metabolism and pharmacokinetics in children and the elderly

In drug development, clinical trials are commonly carried out in either healthy volunteers or carefully selected patients. However, it has been recognised for a long time that both extremes of age, children and elderly, display a number of important metabolic and pharmacokinetic differences as compared with adults. This also has important consequences as to the toxic reactions and risk assessment of chemicals. What is known, what is not known and what should we do to improve the situation?     

Single dose pharmacokinetics and pharmacodynamics of oral loprazolam in the elderly.

The pharmacokinetics of the benzodiazepine hypnotic, loprazolam (1.0 mg orally), and the pharmacodynamic response to single oral doses (0.5 mg and 1.0 mg) have been compared in young and elderly healthy volunteers. No difference between the groups in peak plasma concentration (Cmax) or in the time to peak (tmax) was found, but the elimination half-life t1/2,z and area under the plasma concentration-time curve (AUC) were significantly greater in the elderly group. The immediate effects of loprazolam on all three performance tests used (postural sway, critical flicker fusion threshold (CFFT) and choice reaction time (CRT] and on subjective sedation tended to be more pronounced in the elderly subjects, though intersubject variability in response was high in both groups. The corresponding plasma concentrations did not differ significantly between the two groups. The higher (1.0 mg) dosage was associated with significant residual (11 h) impairment of standing steadiness in the elderly subjects. No other hangover effects were observed. The results are compatible with previous evidence of increased 'sensitivity' to benzodiazepines in the elderly and suggest that a lower (0.5 mg) starting dose of loprazolam would be appropriate for older recipients. Further investigation would be necessary to establish whether clinically relevant accumulation of loprazolam occurs in the elderly following repeated dosage.     

Chronic dose urinary and serum pharmacokinetics of norfloxacin in the elderly.

1. Norfloxacin was administered as two daily 400 mg oral doses to eight elderly patients requiring treatment for urinary tract infections. Blood specimens were obtained for pharmacokinetic profiles following the first and fifteenth doses. Further specimens were obtained before each morning's dose of norfloxacin. Specimens of urine were obtained to ascertain if adequate antimicrobial concentrations were reached in these patients with diminished renal function. 2. Norfloxacin half-life was consistent with that expected in mild renal impairment and was not different between the first and fifteenth doses. Based on ratios of AUC values, accumulation is probably related to renal function, being greatest for creatinine clearance values below 30 ml min-1. 3. On the great majority of occasions, the urinary concentrations of norfloxacin exceeded 20 micrograms ml-1. On days 2-7, the mean percentage 12 h renal elimination of norfloxacin was 18.6 +/- 1.47 (mean of 82 separate observations). Norfloxacin 400 mg twice daily was well tolerated in this group of elderly patients and produced adequate antimicrobial concentrations in urine.     

Oxaprozin dose proportionality

Twelve normal subjects each received single 300-, 600-, and 1200-mg oral doses of oxaprozin according to a three-period crossover design. Total drug plasma concentrations did not increase in proportion to the dose administered. Total clearance (CIo) and volume of distribution (Vd) increased with dose, though elimination t1 2 remained unchanged. The fraction of unbound oxaprozin in plasma (fup) varied linearly with total plasma concentration: it increased from 0.068 per cent at 10 micrograms/ml to 0.180 per cent at 170 micrograms/ml. A parameter fup was therefore introduced to express the average degree of unbound drug plasma for a given dose, and to allow the calculation of unbound volume of distribution (Vdu) and intrinsic clearance (CIi) as if binding were constant. Even though fup increased with dose, the overall binding in the body (fub approximately 0.52 per cent) was relatively stable. Neither Vdu nor CIi changed with dose; hence, unbound oxaprozin kinetics can be considered to be linear. Protein binding had no effect on unbound oxaprozin plasma levels within the given dose range, and there was a one-to-one proportionality between the dose administered and the unbound drug concentration in plasma.     

红霉素在老年人中的药物动力学

目的:研究红霉素(ERY)在老年人体内过程的特点.方法:以年轻志愿者为对照,研究ERY在老年人中的药物动力学.10名老年志愿者(老年组)和8名年轻志愿者(年轻组)分别单剂量空腹po ERY肠溶微粒胶囊500 mg后采用微生物法测定血、尿药物浓度,计算药物动力学参数.结果:老年组po ERY 500mg后其c_(max)、t_(max)、T_(1/zβ)和AUC分别为3.04mg/mg/L、2.98h、2.55h和14.58(mg/L)·h,给药后24h时累积尿排出率为4.28%.结论;老年组poERY后吸收较年轻组为缓慢,AUC值较年轻组增高.两组间差异有统计学意义(P<0.05),c_(max)、T_(1/zβ)和尿排出率等两组间差异无统计学意义(P>0.05).     

薄层色谱法检测奥沙普秦中的有关物质

目的：建立奥沙普秦中有关物质的鉴别方法。方法：用薄层色谱仪检测有关物质。结果：该方法简便、灵敏、可靠。结论：本方法可作为奥沙普秦中有关物质的质量控制。     

The pharmacokinetics and pharmacodynamics of quinine in the diabetic and non-diabetic elderly.

1. Quinine is a front-line antimalarial drug but is prescribed most commonly in nonmalarious countries for cramps. Postural hypotension, hearing loss and hyperinsulinaemic hypoglycaemia occur in malaria and overdose but little is known of quinine kinetics and toxicity in the elderly. 2. We studied 12 non-insulin-dependent diabetics and 10 non-diabetic controls aged 51-79 years. Subjects attended on two occasions > 7 days apart. On each test day, subjects were given a 600 Cal meal at 18.00 h (0 h) and, on one occasion, quinine sulphate 600 mg at 22.00 h (4 h). Venous blood samples for glucose, insulin and quinine assay were drawn pre-prandially and then regularly over the next 38 h. Supine and erect blood pressures were taken and audiometry was performed at 4, 6, 8 and 14 h. A one-compartment open pharmacokinetic model was fitted to serum quinine concentrations. 3. Absorption and elimination half-times, volume of distribution and oral clearance of quinine were comparable in the two groups (P > 0.2) and there was a mean absorption lag-time of approximately 1 h. Basal and immediate post-prandial (< 4 h) serum glucose and insulin concentrations on both test days were similar in the diabetics and also in the non-diabetics, but quinine produced a mean reduction in serum glucose of 1.0 mmol l-1 from 3-5 h post-dose in both groups without affecting serum insulin concentrations. Quinine administration did not alter postural blood pressure changes or produce significant hearing loss in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly.

Ondansetron is a 5-hydroxytryptamine3 receptor antagonist for the treatment of chemotherapy- and radiotherapy-induced nausea and emesis. A sensitive, accurate, and precise HPLC method for the determination of ondansetron in plasma is described. Samples are prepared by solid-phase extraction and, after chromatography of the extracts on a silica analytical column, ondansetron is detected by UV absorbance at 305 nm. The method is sensitive down to 1 ng/mL, at which concentration the coefficient of variation was 6.2% in a single assay run. Repeated analyses of quality control samples, nominally at 2 ng/mL, were carried out over a number of assay runs with a coefficient of variation of 5.5%. The method is specific for ondansetron with respect to endogenous plasma components, identified phase I metabolites, and some co-administered chemotherapeutic drugs. In sustained use over several months, and in support of the clinical development of ondansetron, the method has been shown to be robust. An application of the assay in the investigation of the pharmacokinetics of ondansetron in the young and elderly is described.