The effect of ageing on the pharmacokinetics of dihydrocodeine

Summary Although poor renal function reduces clearance of dihydrocodeine in man, and renal impairment occurs with ageing, no significant differences occurred in the handling of single doses of dihydrocodeine between elderly patients and young, normal subjects.After multiple dosing, the maximum concentration was significantly different between the groups, being higher in the elderly. The increase in the area under the curve in the elderly was 25% greater than in the young on chronic therapy. This difference was not statistically significant, but was likely to be of clinical significance.The elderly patients' mean creatinine clearance (61.8 ml per min) was significantly lower than that in the young (137 ml per min), and there was a significant correlation between the half-life at single dosing and the blood urea concentration.Variability in all measurements was marked in both groups, and hence no clear guidelines can be given on therapeutic dosing. The small initial dose with alterations thereafter depending on clinical effect is the best advice.     

The effect of age on the pharmacokinetics of enoxacin

Summary We have studied the pharmacokinetics of enoxacin in two groups of subjects, 10 young (18–45 years) and 10 elderly adults (>65 years) after a single oral dose of enoxacin (600 mg). Enoxacin was absorbed rapidly, peak plasma concentrations being reached within two hours in both groups. However, the peak plasma concentration of enoxacin was significantly higher in the elderly than in the young adults. The area under the concentration-time curve extrapolated to infinity was also significantly greater in the elderly compared with the young subjects, and the apparent renal clearance was significantly less in the elderly than in the young adults. Consequently, the urinary elimination of unchanged enoxacin was significantly reduced in the elderly. The apparent volume of distribution in the elderly was significantly less than in the young adults. The elimination half-time of enoxacin was similar in the two groups.     

The effect of age on the pharmacokinetics of the opioid antagonist nalmefene

1 The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1  mg ( n =18 young; n =11 elderly) or 2  mg ( n =8 young; n =15 elderly) intravenous bolus dose of nalmefene.
2 Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1  l  kg⁻¹ for 1  mg dose). The elderly volunteers also had a significantly shorter distributional half-life ( t1/2λ1 ) than young volunteers (0.7±0.7 vs 1.3±0.8  h for 1  mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution.
3 Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.     

Single dose pharmacokinetics of sumatriptan in healthy volunteers

Sumatriptan is classified as a vascular 5HT₁ receptor agonist and is effective in the acute treatment of migraine and cluster headache. Sumatriptan is available as an injection for subcutaneous administration and as a tablet for oral administration. The pharmacokinetics of sumatriptan differ depending on the route of administration.The mean subcutaneous bioavilability is 96% compared to 14% for the oral tablet. The lower bioavailability following oral administration is due mainly to presystemic metabolism. The inter-subject variability in plasma sumatriptan concentrations is greater following oral administration and a faster rate of absorption of drug into the systemic circulation is achieved following subcutaneous dosing. The pharmacokinetics of sumatriptan are linear up to a subcutaneous dose of 16 mg. Following oral dosing up to 400 mg, the pharmacokinetics are also linear, with the exception of rate of absorption, as indicated by a dose dependent increase in time to peak concentration.Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism to the pharmacologically inactive indoleacetic acid analogue. Both sumatriptan and its metabolite are excreted in the urine. Although the renal clearance of sumatriptan is only 20% of the total clearance, it exceeds the glomerular filtration rate, indicating that sumatriptan undergoes active renal tubular secretion. Sumatriptan has a large apparent volume of distribution (170 1) and an elimination half-life of 2 h.Oral doses of sumatriptan were administered as a solution of dispersible tablets and subcutaneous dosing was by injection into the arm. In clinical practice, sumatriptan is administered as a film coated tablet or by subcutaneous injection into the thigh.     

The effect of exercise on atropine pharmacokinetics

Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO₂ max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1.Ex prior to atropine (T2) significantly decreased the mean volume of distribution (V_z, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t_1/2, 4.2 vs 3.5 h), V_z (278 vs 1981), and clearance (CL, 763 vs 638 ml·min^–1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml^–1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml^–1). In T5, Ex significantly decreased the t_1/2 (3.4 h), V_z (182 l) and CL (575 ml·min^–1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min^–1), elimination rate constant (ke, 0.0012 vs 0.0015 min^–1), C_p (14 ng·ml^–1) and AUC (53.3 ng·h·ml^–1).These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.Portions of this work were presented at the annual meeting of The American Society for Pharmacology and Experimental Therapeutics, Montreal, Canada, October 1988The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the opinions of the Department of the Army or the Department of Defense.     

Comparative pharmacokinetics of ceftazidime in young,healthy and elderly,acutely ill males

Summary The pharmacokinetics of ceftazidime have been investigated after single and multiple i.v. doses in 9 young healthy male volunteers and 15 elderly male patients with acute bacterial infections. All subjects had normal, age-correlated glomerular function.Distribution and elimination in young volunteers were unaffected by posture and were similar to what has been reported earlier. In contrast, elderly patients had longer t_1/2 (3.1 vs 1.9 h), larger AUC (414.0 vs 276.6 h·mg/l), lower total and renal clearances, reduced urinary recovery over 12 h and enlarged V_ss. Total serum clearance of ceftazidime was closely correlated with the⁵¹Cr-EDTA clearance. There was no significant change in⁵¹Cr-EDTA clearance after seven days of treatment.A reduction in the dose of betalactam antibiotics eliminated by the kidney is advisable in elderly patients with an acute bacterial infection.     

脑心通胶囊对缬沙坦在大鼠体内药动学的影响

目的 研究脑心通胶囊对缬沙坦在大鼠体内药动学的影响。方法 建立液相色谱-串联质谱（LC-MS/MS）法检测缬沙坦血药浓度,并进行专属性考察、回收率试验、基质效应、稳定性试验等方法学验证;24只SD雄性大鼠,随机均分为3组,每组8只,分别为缬沙坦组（A组）,缬沙坦和脑心通胶囊单次给药组（B组）,脑心通胶囊给药7 d后,第8天ig给予缬沙坦和脑心通胶囊组（C组）,于给药前及给药后不同时间点由大鼠眼眶静脉丛采血,采用液相色谱-串联质谱（LC-MS/MS）法测定血浆中缬沙坦的质量浓度,DAS2.0软件统计分析,得到缬沙坦的药动学参数。结果 成功建立LC-MS/MS法检测缬沙坦血药浓度方法,方法学验证符合药动学相关规范要求。口服缬沙坦在大鼠体内的药动学属于一室模型。B组C_max明显低于A组,但差异无统计学差异;B组t_1/2显著高于A组（P<0.05）;C组t_max、t_1/2、AUC_0-tn、AUC_0-∞均显著高于A组（P<0.05、0.01）,K_e显著低于A组（P<0.05）;C组AUC_0-tn、AUC_0-∞显著高于B组（P<0.05）。结论 大鼠经连续ig给药脑心通胶囊后,可显著延缓缬沙坦在大鼠体内的达峰时间,并使缬沙坦在大鼠体内的生物利用度升高。     

Effect of age on the pharmacokinetics of vinpocetine (Cavinton) and apovincaminic acid

Summary The pharmacokinetics of vinpocetine and its main metabolite, apovincaminic acid (AVA), were studied in the aged. Vinpocetine was eliminated with a mean half-life of 2.12±0.51 h. Total plasma clearance (CL) and distribution coefficient () of the parent drug were 2.2±0.9 l · kg^–1 · h^–1 and 6.7±3.7 l · kg^–1, respectively. The CL and of vinpocetine differed significantly from young subjects but the elimination half-life was not altered. Significant changes in the elimination half-life and plasma clearance of AVA were found, perhaps because of the physiological decrease in renal function.     

The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers

The pharmacokinetics and psychomotor effects of medifoxamine, a 5 HT reuptake inhibitory antidepressant, were studied in healthy elderly volunteers after single and multiple dosing.The elimination half life (t1/2z) after single doses of 300 mg was 2.8 h — almost identical to that found in young volunteers. After seven days of dosing at 100 mg three times daily the mean corrected AUC after 300 mg significantly increased from 1.04 to 1.34 mg.h.l^–1 and t1/2_z increased to 4.0 h (NS).There were no significant changes in critical flicker fusion frequency, symbol digit substitution, continuous attention or choice reaction times.     

Single and multiple dose pharmacokinetics of tenoxicam in the elderly

Summary Fourteen elderly subjects (10 women, 4 men) with a mean age of 81 (SD 6.7) years and in need of anti-inflammatory drug treatment were given a single dose of 20 mg tenoxicam. After a drug-free interval of 5 weeks, multiple dose treatment with 20 mg tenoxicam once daily for 56 days was initiated. The single and multiple dose kinetics of tenoxicam were investigated after HPLC determination of tenoxicam in the plasma.The elimination half-life of tenoxicam ranged from 44 to 132 h (mean 71.9 h) with no significant difference between the single and multiple dosage regimens. Tenoxicam reached maximum plasma concentrations after 1.4 and 1.1 h, with values of 3.6 and 15.5 µg·ml^–1, for the single and multiple dosage regimen respectively. The corresponding trough values (24-h values) were 1.8 and 11.7 µg·ml^–1. A mean accumulation ratio of 5.1 was calculated. The mean increase in the area under the plasma concentration time curves at steady-state was 21% more than predicted from the initial single dose. This deviation from linearity was considered to be of minor clinical significance. The kinetics of tenoxicam in elderly were similar to that published for young healthy volunteers.     

缬沙坦治疗老年高血压的临床观察

目的观察缬沙坦治疗老年高血压的疗效。方法将该院112例老年高血压患者分为治疗组54例和加服缬沙坦58例。结果与治疗前比较,治疗后患者SBP改善,差异有统计学意义（P〈0.05）,缬沙坦治疗组改善情况明显优于对照组（P〈0.05）。缬沙坦治疗组总有效率为96.55%,明显高于对照组的92.59%,差异有统计学意义（P〈0.05）。结论缬沙坦联合治疗老年高血压病安全的、有效的,是比较理想的老年性高血压降压药物。     

Effect of age on the pharmacokinetics of duloxetine in women

AIMS: The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence. METHODS: Twenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentration-time data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24-77 years) who received duloxetine 20 mg day(-1), 30 mg day(-1), or 40 mg day(-1) in Study 2A and 128 women (28-64 years) who received duloxetine 20 mg day(-1), 40 mg day(-1), or 80 mg day(-1) in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed-effects modelling program (NONMEM). RESULTS: In Study 1, the elderly (> or = 65 years) exhibited a statistically significant slower elimination rate constant lambdaz compared with younger subjects [elderly-younger difference = -0.022 h(-1)[95% confidence interval (CI) -0.036, -0.008]]. However, no statistically significant differences in either CL/F [elderly-younger difference = -17.4 l h(-1) (95% CI -41.1, 6.23)] or V/F [elderly-younger difference = 115.9 l (95% CI -168.6, 400.4)] were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non-elderly participants in these studies. CONCLUSIONS: Whereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower lambdaz in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted.     

Analysis of the pharmacokinetics of lithium in man

Summary An analysis of the single and multiple dose pharmacokinetics of lithium in 7 healthy volunteers is presented. A solution of lithium chloride was administered in single dose experiments and the same solution and a sustained release preparation were employed in multiple dose experiments, which were carried out at steady state. A fixed dose of 24 mmol was used in the single dose experiments and in the subsequent multiple dose experiments in the same subjects the same dose was administered once daily for a week. Distinct two-compartment characteristics were found, with a mean disposition rate constant () of 0.035 h^–1±0.010 SD, corresponding to a mean biological half-life of about 19.8 h. The mean half-time of the distributory -phase was about 1.15 h. The absorption of lithium from an orally administered solution took place with a half-time of about 0.15 h in the single dose experiments. The apparent volume of distribution of the central compartment (V_c) was 0.307 1 kg^–1±0.046 SD, less than half that of V_de at equilibrium. V_d (V_darea) was 0.8291 kg^–1±0.184 SD and mean total body clearance was 27.6 ml kg^–1 h^–1±4.7 SD.     

短期合用缬沙坦与盐酸贝那普利对高血压患者药代动力学与药效学的影响

目的探讨短期合用缬沙坦与盐酸贝那普利（抗高血压药）的药代动力学与药效学.方法16例原发性高血压病人分为缬沙坦单用组和联合用药组,单用组口服缬沙坦每天80 mg,合用组口服缬沙坦每天80 mg、盐酸贝那普利每天10 mg,2组均连服7天;测定服药第7天缬沙坦血药浓度;观察服药前后24 h动态血压、肾素-血管紧张素-醛固酮系统（RAAS）各组分、肾功能及血钾变化.结果主要药代动力学参数Cmax,tmax,t1/2,AUC 2组比较均无统计学差异;服药后,降压幅度合用组显著优于单用组;短期服药后,2组RAAS系统各组分变化均无统计学意义;服药后,肾功能及血钾单用组无显著变化,合用组血钾显著降低,但变化在临床正常范围内.结论短期合用盐酸贝那普利对缬沙坦药代动力学参数无显著影响;合用降压作用起效快,降压幅度优于单用缬沙坦,且较安全.     

Influence of age, frailty and liver function on the pharmacokinetics of brofaromine

Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y). Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 mol*h·l^–1, clearance was reduced (5.0 vs. 11.8 l·h^–1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r=0.41, P=0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r=0.94, P<0.0001). Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.     

A comparative study of the pharmacokinetics and pharmacodynamics of atenolol,hydrochlorothiazide and amiloride in normal young and elderly subjects and elderly hypertensive patients

Summary Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.     

福辛普利联合缬沙坦对梗阻性肾病模型幼鼠MMP-7表达的影响

目的:观察联合应用福辛普利和缬沙坦对梗阻性肾病模型(UUO)大鼠肾小管间质MMP-7表达的影响,初步探讨其在肾间质纤维化中的作用机制。方法:72只Wistar雌性幼年大鼠单侧输尿管结扎制成UUO模型,并随机分为假手术对照组(A组)、UUO模型组(B组)和福辛普利及缬沙坦联合治疗组(C组),于模型成功后第1,2,3,4周末为实验时间点,检测各组大鼠24h尿蛋白、血尿素氮(BUN)、血肌酐(SCr)。用免疫组化法研究MMP-7在肾组织的分布、表达及变化。结果:光镜下MMP-7在对照组肾小管上皮细胞胞浆呈阴性表达,术后1周UUO组MMP-7在肾小管上皮细胞胞浆区及肾间质细胞表达,在血管内皮细胞有微量表达,2周后表达增强,4周表达最强。治疗组各周MMP-7表达较UUO组下调。结论:联合应用福辛普利和缬沙坦可通过下调MMP-7在肾组织的表达而改善肾功能,延缓肾间质纤维化的进展。     

Comparative single dose and steady-state pharmacokinetics of bevantolol in young and elderly subjects

Summary The pharmacokinetics of bevantolol were examined following single and repeated oral doses to young and elderly volunteers. Following administration of a single 200-mg bevantolol tablet mean maximum plasma bevantolol concentrations in young and elderly subjects were 1690 ng/ml and 1810 ng/ml, respectively. Maximum bevantolol concentrations occurred approximately 1.1 h postdose in both young and elderly subjects. There were no significant differences in mean steady state bevantolol concentrations on Day 14 between young and elderly subjects. However, disproportionate increases in C_max, and in AUC, but not in t_max values were observed between Days 1 and 14.On Days 1 and 14, most young and elderly subjects exhibited monoexponential decline in bevantolol plasma concentrations after absorption phase. In those subjects Day 14 elimination half-lives in young and elderly were 1.9 and 2.2 h, respectively. In subjects who exhibited biexponential decline in bevantolol, an age effect in elimination became apparent, on Day 14 elimination half-lives were 5.7 and 11.2 h in young and elderly subjects, respectively. Bevantolol Metabolite III concentrations were observed in plasma of some subjects during the first 6 h after dosing. At steady-state AUC (0-ldc) values for the metabolite were less than 2% those of bevantolol.Bevantolol plasma levels accumulate to a small extent with repeated 200 mg daily doses. This is probably due to the contribution of a late and more persistent terminal elimination phase that was discernable in only certain individuals.     

Dose dependent pharmacokinetics of midazolam

Summary The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the C_max and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t_1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This ist not expected to have any clinical significance under the conditions of therapeutic use.     

家犬单剂量和多剂量口服阿昔莫司缓释制剂的药代动力学和生物等效性研究

目的研究阿昔莫司缓释片在家犬体内单剂量和多剂量的药代动力学和生物等效性。方法测定6只家犬单剂量和多剂量口服缓释片和普通胶囊后的血药浓度。结果阿昔莫司的药-时曲线符合非隔室模型。单剂量给药后，缓释片和普通胶囊的AUC分别为(158±30)和(147±37) μg·h·mL^-1；T_max分别为(4.3±0.8)和(2.6±1.3) h；C_max分别为(29±6)和(42±10) μg·mL^-1；T_1/2分别为(2.3±0.7)和(1.60±0.10) h；MRT分别为(6.0±0.8)和(3.9±0.7) h；F_r为(108±16)%。多剂量给药后，缓释片和普通胶囊的AUC分别为(209±23)和(195±26) μg·h·mL^-1；T_max分别为(6.3±0.8)和(3.4±1.5) h；C_max分别为(27±4)和(36±5) μg·mL^-1；Cmin分别为(2.2±1.0)和(0.20±0.20) μg·mL^-1；C_av分别为(8.7±1.0)和(8.1±1.1) μg·mL^-1；FI分别为(293±73)%和(448±91)%；F_r为(114±19)%。结论单剂量实验的双单侧检验结果表明：缓释片和普通胶囊生物等效；缓释片具有良好的缓释效果。多剂量实验结果表明：缓释片和普通胶囊生物等效；缓释片的波动系数优于普通胶囊。