Comparative pharmacokinetics and cardiovascular effects of tiapamil in healthy volunteers and patients with hepatic cirrhosis

Summary Tiapamil 70 mg was administered i.v. to 8 healthy male volunteers and 8 patients (7 males, 1 female) with biopsy proven hepatic cirrhosis. Two of the patients also received 600 mg p.o. Serial plasma and urine samples were collected and the parent drug in plasma and urine and desmethyl-tiapamil in urine were assayed by a specific HPLC method. The plasma and urine data for the parent drug after i.v. and p.o. dosing were simultaneously fitted to linear p.o. and i.v. two compartment models with exit from and input into the central compartment. Absorption was assumed to be a first order process. In the volunteers the mean pharmacokinetic parameters were: 101 l for the steady-state volume of distribution, 750 ml·min^–1 for nonrenal clearance, 195 ml·min^–1 for renal clearance and 1.7 h for the half-life of the terminal disposition phase. The urinary recoveries of the parent drug and desmethyltiapamil averaged 21.4 and 0.8% of the dose, respectively. In the patients the steady-state volume of distribution, the amount of unchanged drug in urine and the half-life of the terminal disposition phase were significantly increased (171 l, 29.0% of the dose, 3.5 h, respectively). Decreased plasma protein binding in the patients accounted for the larger steady-state volume of distribution. The nonrenal clearance of 519 ml·min^–1, tended to be smaller in the patients than in the volunteers. Together with the increased urinary recovery of tiapamil in the patients this indicates a moderately impaired elimination capacity in the cirrhotics. The renal clearance was similar in the patients (213 ml·min^–1) and the volunteers. The absolute oral bioavailability of tiapamil was 55 and 49% in 2 patients. No effects of tiapamil on heart rate or supine blood pressure were detected, either in volunteers or in patients. Negative dromotropic effects were found in 2 volunteers and 2 patients after i.v. dosing.     

Comparison of the short-term effects of the loop diuretic piretanide and furosemide in patients with renal insufficiency

Summary The natriuretic effect of the new loop diuretic piretanide was investigated in patients with severe renal insufficiency and was compared with that of furosemide. In the first study 4 hospitalized patients (serum creatinine 407 to 1220 µmol/l) were examined after administration of piretanide (12, 24, 48 and 96 mg to two patients, and 24, 48, 96 and 192 mg to 2 other subjects, given every third day). In the second study 6 hospitalized patients (serum creatinine 194 to 698 µmol/l) were studied after receiving orally 2 different doses of piretanide and 2 different doses of furosemide orally, given every fourth day. The mean natriuretic effect of 48 mg and 96 mg piretanide was 250 and 340% of the control value for the entire group, and 311 to 480% in the subgroup of patients with serum creatinine below 530 µmol/l. For a given dose the natriuresis was inversely correlated with renal function, and at a given serum creatinine level the natriuretic response was dose-dependent. The drug had less effect on water and potassium diuresis than on natriuresis. No significant difference in natriuretic effect was found on comparison with furosemide given in the ratio furosemide: piretanide 3.33:1. The pharmacokinetic data showed a direct correlation between the dose and the mean plasma concentration and also between urinary recovery of the drug and the measured natriuretic response.     

Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver

Summary The pharmacokinetics of chlormethiazole after oral and intravenous administration was studied in six healthy volunteers and eight patients with alcoholic cirrhosis of the liver. Plasma concentration-time curve after the intravenous infusion could adequately be described by two- or three-compartment open models both in healthy volunteers and in the patients. Based on the areas under the plasma concentration-time curves, the systemic bioavailability of oral chlormethiazole was about ten times greater in the patients than in healthy controls. The elimination of chlormethiazole was relatively less retarded in the patients, as indicated by a decrease of about 30% in its plasma clearance. In the patients the plasma protein binding of chlormethiazole was decreased, but the volume of distribution and half-life of elimination were unchanged. The increase in bioavailability of chlormethiazole was associated with significant alteration in the serum levels of bilirubin, albumin, alkaline phosphatase, prothrombin-proconvertin activity (P + P) and elimination rate of antipyrine or¹⁴C-aminopyrine. The increased bioavailability of oral chlormethiazole was due to impaired first-pass metabolism in the cirrhotic liver. A considerable reduction in dose seems to be indicated if oral chlormethiazole is used in patients with advanced cirrhosis of the liver. A substantial fraction of dose, averaging 15%, was lost during the intravenous infusion, presumably due to adsorption to the infusion tubing.     

Pharmacokinetics of meptazinol after parenteral administration in the elderly

Summary We have determined the pharmacokinetics of meptazinol after its intravenous and intramuscular administration in a crossover study in 7 elderly hospital in-patients (>70 years), and have compared with the results from 14 healthy, young volunteers (ages 20–40 years). The systemic availability after i.m. administration was comparable to that after i.v. administration, a result consistent with the physicochemical properties of the drug. There was a slight, but statistically significant (p<0.01) prolongation in t_1/2z in the elderly (mean 2.93 h) compared with the young (mean 2.06 h). This was associated with a 25% lower clearance in the elderly rather than with any alteration in volume of distribution. However, these changes would not appear to be substantial enough to require a revised dosage recommendation for meptazinol for this age group.     

Pharmacokinetics/pharmacodynamics of furosemide in man: A review

The pharmacokinetics of furosemide and the attempt to correlate biological fluid measurements with diuretic response have been the subject of a large number of studies since the original reports of HajdÚ, Rupp, and coworkers in the mid-1960s. This article attempts to critically review these studies under seven different sections: furosemide pharmacokinetics in normal volunteers, furosemide pharmacokinetics in patients with decreased renal function, furosemide pharmacokinetics in patients with congestive heart failure, furosemide metabolism and assay methods, furosemide bioavailability, dose-response relationships, and the role of inhibitors and mediators on furosemide effects. The literature is reviewed through August 1978.     

Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide

Summary After rapid intravenous injection of furosemide 40 mg (Fu), plasma levels were determined in 7 healthy volunteers, 8 patients with liver cirrhosis with ascites and 7 patients with end-stage renal disease (ESRD). The diuretic response was evaluated by measuring the urinary excretion of sodium and potassium and the urine volume. The mean elimination half life (tF_1/2+) of Fu averaged 51±7.7 (±SD) min in healthy subjects, 52±7.7 min in cirrhosis and 200±57 min in ESRD. The non-renal clearance (Cl_nr) in healthy subjects (56±28 ml/min) corresponds to the total plasma clearance in functionally anephric patients (54±18 ml/min). In cirrhosis there was no significant change in the disposition parameters of Fu in comparison to the healthy volunteers, but there was a significant reduction in urine sodium and volume, whereas potassium excretion remained unchanged. Fu “excretion rate — response” curves showed diminished tubular sensitivity to Fu in cirrhosis. Preliminary results were reported at the 86th Annual Meeting of the Deutsche Gesellschaft für Innere Medizin     

Pharmacokinetics of exogenous adenosine in man after infusion

Summary The plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 g·kg^–1 respectively) and after infusion of 200 g·kg^–1 in 10 min followed by 400 g·kg^–1 in 10 min.As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min^–1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l).After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 g·ml^–1), but the mean clearance and half-life were significantly different (12.1 l·min^–1 and 0.63 min respectively).In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.     

Pharmacokinetics of ofloxacin in elderly patients and in healthy young subjects

Summary The pharmacokinetics of ofloxacin, a fluoroquinolone widely used in the treatment of bacterial infections, may be different according to age, owing to the biological differences that exist between an elderly organism and a young subject, expecially as regards the renal and the hepatic function.In our study the pharmacokinetics of ofloxacin in 12 elderly patients was found to be different from those of 12 healthy young volunteers.The elimination half-life (t_&frac;) was slightly shorter in the young subjects than in the elderly: 6.2 (0.9)h against 8.5(1.2)h respectively. The oral total clearance was lower in the geriatric patients compared to the young healthy volunteers: 83.3(16.6) ml/min in the first group, and 23.3(33.3) ml/min in the second group. AUC and peak plasma concentration in elderly exceeded those noted in young healthy volunteers.The results of this study suggest that, compared with younger subjects, older patients experience delayed elimination of ofloxacin. It would be reasonable, from a pharmacokinetic point of view, to limit the dose of ofloxacin in patients more than 75 years old, at least to one half of that given to younger patients.     

Pharmacokinetics of high doses of piretanide in moderate to severe renal failure

Summary The pharmacokinetics of piretanide was studied in 10 patients with chronic renal failure. After administration of a high oral dose (12 to 192 mg) of piretanide the kinetics behaved according to an open 2-compartment model. The elimination constant in the first phase () ranged from 0.385 to 0.756 h^–1 and in the second phase () from 0.079 to 0.274 h^–1. The corresponding elimination half-lives ranged from 55 to 108 min (t_1/2 ) and from 152 to 524 min (t_1/2 ). Only an average of 2.8% of the orally administered drug was recovered in 24 h urines. Nevertheless, a good correlation was found between urinary recovery or renal clearance of the drug and residual renal function. The elimination of piretanide by non-renal mechanisms appeared to be increased when renal function was greatly diminished.     

Pharmacokinetics of furosemide in anephric patients and in normal subjects

Summary The pharmacokinetics of furosemide 40 mg i.v. were compared in 7 anephric patients and in 7 normal subjects. The average serum clearance was 66 ml/min in the patients and 219 ml/min in the normal subjects, and the corresponding weight corrected clearances were 1.33 ml/min · kg and 2.96 ml/min · kg. Binding to serum proteins was significantly decreased in the anephric subjects, in whom a significant negative correlation was found between the percentage binding and the volume of distribution V_Dss. In the patients, but not in the normal subjects, there was a significant positive correlation between and serum clearance. Both in normal and anephric individuals 4-chlor-5-sulphamoylanthranilic-acid (CSA) was found, but there was no evidence of special accumulation either of CSA or anthranilic acid in the anephric patients. In the patients the initial increase in serum concentration of sodium and protein followed by a more conspicuous decrease were more pronounced, but none of the changes were statistically significant.     

Pharmacokinetics of nicardipine enantiomers in healthy young volunteers

Objectives: The present study was conducted to compare pharmacokinetic behaviors of nicardipine enantiomers given in different doses with different formulations of racemic nicardipine in healthy volunteers. Methods: One or two 20-mg racemic nicardipine tablets, and a 40-mg sustained-release capsule of nicardipine were administered to eight healthy volunteers in a cross-over fashion and pharmacokinetic parameters were evaluated. Enantiomer concentrations were determined by GC-MS combined with chiral stationary phase HPLC. Results and conclusions: Serum concentration of (+)-nicardipine was approximately 2–3 times higher than that of (−)-nicardipine in 20- and 40-mg doses of conventional formulations and a non-linear increase in bioavailability with dose was demonstrated. The value for AUC of (+)-nicardipine was approximately 2.3–2.8 times greater than that of the (−)-nicardipine (P < 0.05) when 20 and 40 mg racemic nicardipine were administered in a conventional preparation. Relative bioavailability of the sustained-release preparation vs the conventional preparation was 28% and 44% for (+)- and (−)-nicardipine, respectively, for the 40-mg dose. Received: 23 September 1996 / Accepted in revised form: 23 February 1997     

Pharmacokinetics of hexobarbital in man after intravenous infusion

The plasma levels of hexobarbital in humans were determined during and after a 30-min or 60-min zero-order intravenous infusion. Hexobarbital kinetics could be described by conceiving the body to exhibit two compartments. The plasma concentrations were fitted to the postinfusion equation and the parameters intrinsic to the two- compartment open model were estimated. The elimination half-life varied considerably among the 14 individuals (160–441 min), which could mainly be explained by the greatly varying metabolic clearance of the compound (123–360 ml /min). The apparent volume of distribution per kilogram of body weight was relatively constant (1.10±0.12 liters/kg).This work was supported in part by a grant from the Netherlands Foundation for Medical Research FUNGO.     

Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition

The influence of dietary protein deficiency on pharmacokinetics and pharmacodynamics of furosemide was investigated after iv bolus (1 mg/100 g) and oral (2 mg/100 g) administration of furosemide to male Sprague-Dawley rats fed on a 23% (control) or a 5% (protein-calorie malnutrition: PCM) protein diet ad lib.for 4 weeks. After iv administration, the mean values of CL _R , V _{ss, and the percentages of dose excreted in 8-hr urine as furosemide were increased 81, 31, and 61%, respectively, in PCM rats when compared with those in control rats, however}, CL _NR was 54% decreased in PCM rats. The decreased CL_NR in PCM rats suggested the significantly decreased nonrenal metabolism of furosemide. The urine volume per g kidney after iv administration was not significantly different between the two groups of rats although the amount of furosemide excreted in 8-hr urine per g kidney increased significantly in PCM rats. The diuretic, natriuretic, kaluretic, and chloruretic efficiencies reduced significantly in PCM rats after iv administration. After oral administration, the extent of bioavailability increased considerably from 27.6% in control rats to 47.0% in PCM rats, probably as a result of decreased gastrointestinal and hepatic first-pass metabolism. This was supported by a tissue homogenate study; the amount of furosemide remaining per g tissue after 30-min incubation of 50 g of furosemide with the 9000 × gsupernatant fraction of stomach (42.4 vs. 47.9 g) and liver (41.4 vs. 45.9 g) homogenates increased significantly in PCM rats. No significant differences in CL_R and t_1/2 were found between the control and the PCM rats after oral administration. The 24-hr urine volume and the amount of sodium excreted in 24-hr urine per g kidney increased significantly in PCM rats, and this might be due to a significantly increased amount of furosemide reaching the kidney excreted in urine per g kidney.This work was supported in part by a research grant from the Korea Science and Engineering Foundation, 1990–1992.     

合用盐酸黄连素前后环孢素A的人体药动学

目的 :研究健康受试者合用盐酸黄连素 (berberinehydrochloride ,Ber)前后环孢素A(cyclosporinA ,CsA)的动力学过程 ,以分析两药相互作用发生的部位。方法 :6名健康男性志愿者在单剂口服CsA 3mg·kg-1后开始连续服用Ber 30 0mg ,bid× 10d ,最后一次与单剂CsA 3mg·kg 　 -1同时口服。每次口服CsA后即按时采血 ,用FPIA法测定全血CsA浓度 ,并计算出药动学参数。结果 :在健康志愿者合用Ber后 ,CsA的AUC值增加 19.6 % ,差异具非常显著性 (P <0 .0 1)。结论 :推测Ber对CsA的影响部位可能主要在肠道 ,Ber可能增加CsA的吸收或减少肠代谢。     

Pharmacokinetics of (+)-rolipram and (−)-rolipram in healthy volunteers

Summary Plasma levels of S-(+)-rolipram and R-(–)-rolipram in six healthy male volunteers were measured by radioimmunoassay after intravenous injection of 0.1 mg and oral administration of 1.0 mg of the pure enantionmers. Following i.v. treatment, plasma levels of both isomers declined in three phases, with half-lives of 0.2 h, 0.6–0.9 h and 6–8 h. Total clearance was 6 ml · min^–1 · kg^–1. Oral administration of 1.0 mg gave a peak concentration of 16 ng · ml^–1 after 0.5 h. Bioavailability of (+)-rolipram was 77% and of the (–) enantiomer it was 74%. There was no significant difference in C_max, half-life, total clearance or bioavailability between the two enantiomers.     

Pharmacokinetics of cimetidine after subchronic administration

Summary The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26–29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t_1/2 and V were similarly unchanged. However mean renal clearance (CL_R) and f_e were significantly increased following 2 weeks of drug dosing (CL_R 5.41 ml·min^–1 kg^–1; f_e 0.61) compared to control (CL_R 4.00 ml·min^–1·kg^–1; f_e 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml·min^–1·kg^–1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.     

Effect of probenecid on excretion and natriuretic action of furosemide

Summary Furosemide and inulin were given simultaneously by intravenous infusion to nine subjects over 2 h. The concentrations of sodium and of the two drugs in serum (free and protein bound) and in urine were followed during the infusion. In 6 male subjects the investigation was repeated after 3 days of oral treatment with probenecid 500 mg twice daily. Probenecid reduced the average ratio furosemide clearance/inulin clearance from 0.92 to 0.44. In experiments in which no probenecid had been given an average of 2% of the furosemide in urine was excreted by glomerular filtration. In vitro studies showed that the protein binding of furosemide was decreased in the presence of probenecid. The displacing effect of probenecid was confirmed in vivo, and during probenecid treatment glomerular filtration produced an average of 8% of the furosemide excreted by the kidney. The fraction of furosemide excreted by tubular secretion decreased during probenecid treatment from 98.0±0.6% to 91.7±5.6% (p<0.05). Prior to administration of probenecid, the fraction of the filtered sodium recovered from the urine during furosemide administration was 24.7%. Probenecid reduced that fraction to 21.0% (p<0.05). The excretion rate of furosemide appeared to be a better predictor of the natriuretic effect than its plasma concentration. Probenecid caused a significant change (p<0.05) in the regression line relating the log plasma concentration to the natriuretic effect, but it had no effect on the regression line relating the log urinary excretion rate of furosemide to its natriuretic effect. Although the decrease in the furosemide excretion rate during probenecid treatment averaged 25%, the sodium excretion rate was reduced by less than 15%. It is suggested that the natriuretic effect of furosemide is more pronounced if the furosemide molecules enter the tubular lumen at a more proximal level, and it is strongest if they do so by filtration through the glomerulus.     

Pharmacokinetics of metipranolol in normal man

Summary The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6–25 mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20 mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40 mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; t_max 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20 mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of -blocking agents.     

合用盐酸黄连素前后环孢素A的健康人体药动学研究

目的 :研究健康受试者合用盐酸黄连素 (Ber)前后环孢素A(CsA)的动力学过程 ,以分析两药相互作用发生的部位。方法 :6名健康男性志愿者在单剂口服CsA (6mg·kg-1)后开始连续服用Ber 13d(30 0mg·bid-1) ,然后再单剂口服CsA (6mg·kg-1) ,每次口服CsA后即按时采血 ,并用FPIA法测定全血CsA浓度 ,并计算出药动学参数。结果 :合用Ber前后CsA的主要药动学参数Ka 分别为 0 .91± 0 .30h-1和 1.0 9± 0 .35h-1;T1 2 β分别为 6.18± 0 .94h和6.86± 1.2 7h ;AUC0 -2 4 分别为 11.0± 1.6和 10 .6±1.6mg·h-1·L-1;CL(s)分别为 34.3± 6.7L·h-1和36.6± 9.3L·h-1;Tpeak均为 1.5± 0 .6h ;Cmax分别为1.8± 0 .4mg·L-1和 1.9± 0 .3mg·L-1。结论 :在健康志愿者合用Ber前后CsA的药动学参数没有显著差异 ,推测Ber对CsA的影响部位可能主要在肠道。     

Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses

The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (C_max) and area under the curves (AUC) of buspirone and 1-PP on Days D 5 and 10 were higher than on Day D 1. The trough levels (C_min) and AUCs (D 5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher C_max and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers. There was no correlation between the average plasma concentrations of buspirone ( ) and the degree of renal impairment judged by creatinine clearance. An excellent correlation was observed between of buspirone and serum albumin (r=0.862, and P<0.0001) as well as between and bromsulphalein clearance (r=0.678, P<0.0003).In view of high intra-and inter-subject variability in buspirone concentrations, definitive dosing recommendations for patients with compromised renal or hepatic function could not be made, but such patients should initially be dosed cautiously with buspirone.