Pharmacokinetics of bismuth and ranitidine following single doses of ranitidine bismuth citrate

1 The pharmacokinetics of bismuth and ranitidine derived from ranitidine bismuth citrate given in single oral doses ranging from 200  mg to 1600  mg were evaluated in healthy subjects.
2 Bismuth was only minimally absorbed (<0.5% of the amount dosed) after administration of ranitidine bismuth citrate, and peak plasma concentrations never exceeded 33  ng  ml⁻¹ in any subject. Plasma concentrations and urinary recoveries of bismuth at doses up to and including 800  mg were relatively constant and not proportional to dose. Bismuth absorption was increased more than proportionally with the dose at 1600  mg.
3 The pharmacokinetics of ranitidine after administration of ranitidine bismuth citrate were dose-proportional and consistent with previous observations for ranitidine administered alone.
4 Ranitidine bismuth citrate was well-tolerated in single oral doses of up to 1600  mg.     

Pharmacokinetics of bismuth and ranitidine following multiple doses of ranitidine bismuth citrate

1 The pharmacokinetics of bismuth and ranitidine derived from oral doses of ranitidine bismuth citrate 800  mg given twice daily for 28 days were examined in this double-blind, placebo-controlled, parallel-group study in 27 healthy subjects.
2 Bismuth accumulation in plasma reflected its multicompartmental disposition, achieving the majority of predicted steady state within 14–28 days. Bismuth absorption from ranitidine bismuth citrate is limited (<0.5% of the dose), and bismuth elimination is predominantly renal secretion. Peak plasma concentrations did not exceed 19  ng  ml⁻¹, remaining well below those associated with bismuth toxicity. Bismuth was measurable at low concentrations in plasma and urine for up to 5 months after the last dose. Plasma bismuth concentration-time data and urinary excretion data were best described by separate multicompartmental models, with terminal half-lives averaging 21 days and 45 days, respectively.
3 The pharmacokinetics of ranitidine derived from ranitidine bismuth citrate were similar to those of ranitidine administered alone. Ranitidine did not appreciably accumulate in plasma.
4 Ranitidine bismuth citrate was well-tolerated during 28 days of repeated dosing.     

Pharmacokinetics of cephacetrile in patients undergoing haemodialysis

Summary The pharmacokinetics of cephacetrile were studied after its administration as a single i.v. bolus injection of 15 mg/kg body weight to 11 patients with terminal renal inpairment undergoing haemodialysis for 6 h. A two-compartment kinetic model was used to describe the biphasic decrease in plasma concentration. The quantities of antibiotic in the central and peripheral compartments, and the amounts eliminated, were calculated for different times. During haemodialysis sessions, the average pharmacokinetic parameters of cephacetrile determined at the dialyser input were:=5.03 h^–1,=0.458 h^–1, K₁₂=2.337 h^–1, K₂₁=1.996 h^–1 K₁₃=1.154 h^–1, V_c=5.508 l, V_p=6.448 l, Vd_ss=11.956 l.As a function of the pharmacokinetic parameters of cephacetrile, a regimen of multiple doses was established for patients with terminal renal impairment, which will guarantee safe and effective concentrations of the antibiotic.     

血浆中雷尼替丁和铋的药动学和生物等效性研究

目的建立高效液相色谱(HPLC)和电感耦合等离子体-质谱(ICP-MS)分别测定人血浆中雷尼替丁和铋质量浓度的方法 ,并应用该法进行雷尼替丁和铋在健康人体内的药动学特征研究和复方盐酸雷尼替丁片生物等效性评价。方法采用HPLC法和ICP-MS技术,分别测定20名健康男性受试者经口给予复方盐酸雷尼替丁片和复方雷尼替丁胶囊后不同时刻血浆中雷尼替丁和铋的质量浓度,分别绘制血药质量浓度-时间曲线,并计算主要药动学参数。结果受试制剂和参比制剂中雷尼替丁的主要药动学参数如下:tmax分别为(1.9±0.5)和(2.1±0.6)h,ρmax分别为(492.8±276.7)和(466.5±224.4)μg.L-1,t1/2分别为(2.9±1.6)和(2.8±1.0)h,用梯形法计算,AUC0-t分别为(2 548.3±895.6)和(2 377.5±887.0)μg.h.L-1,AUC0-∞分别为(2 562.9±912.8)和(2 377.5±887.0)μg.h.L-1,雷尼替丁的相对生物利用度平均为(111.6±35.4)%。受试制剂和参比制剂中铋的主要药动学参数如下:tmax分别为(0.4±0.2)和(0.3±0.1)h,ρmax分别为(56.0±40.2)和(53.3±37.9)μg.L-1,t1/2分别为(6.9±2.6)和(7.2±2.3)h,用梯形法计算,AUC0-t分别为(151.8±118.9)和(156.3±117.9)μg.h.L-1,AUC0-∞分别为(153.1±120.2)和(157.7±119.3)μg.h.L-1,铋的相对生物利用度平均为(95.3±16.2)%。结论复方盐酸雷尼替丁片与复方雷尼替丁胶囊两种制剂具有生物等效性。     

Elimination of amrinone during continuous veno-venous haemofiltration after cardiac surgery

We studied the elimination of amrinone during continuous veno-venous haemofiltration (CVVHF) in three anuric patients after cardiac surgery. The patients had developed low cardiac output followed by acute prerenal failure. Plasma amrinone levels measured by HPLC were fitted to a two-compartment model.We found significant amrinone clearance, with a mean sieving coefficient (S) of 0.44%, which correlates with the protein-unbound, pharmacologically effective fraction of amrinone. The AUC of the arterial plasma concentration-time curve was decreased by 49.8%. All pharmacokinetic parameters showed wide interindividual variation.To ensure the therapeutic effect of amrinone and to avoid toxic adverse effects monitoring of plasma amrinone levels is necessary.     

Pharmacokinetics of flutamide in patients with renal insufficiency

AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.     

Pharmacokinetics of cefoperazone in patients undergoing chronic ambulatory peritoneal dialysis: Clinical and pathophysiological implications

Summary The pharmacokinetics of cefoperazone after i.p. and/or i.v. administration were studied in 12 CAPD patients. After i.v. injection, the plasma half-life was 2.65±0.4 h, the total clearance amounting to 70.1±19.2 ml/min. Peritoneal clearance was calculated to be 6.9±1 ml/min. After peritoneal instillation, the bioavailability was 63.9±5%. After repeated i.p. administration, no accumulation of the drug in the body was observed. Thus, cefoperazone can be safely administered for the treatment of peritonitis in CAPD patients.     

Pharmacokinetics of quinine in patients with chronic renal failure

Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (t_max 4.5 vs 1.6 h, C_max 6.17 vs 3.45 g·ml^–1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min^–1·kg^–1, whereas V_z/f remained unchanged (1.82 vs 2.78 1·kg^–1). This resulted in the increased values of AUC and prolongation of the t_1/2z and MRT in the patients (AUC 181.5 vs 61.8 g·min^–1·ml^–1, t_1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.     

Pharmacokinetics of carteolol in patients with impaired renal function

Summary In order to determine the appropriate dosage of carteolol in renal dysfunction, the pharmacokinetics of carteolol has been examined in appropriate patients. The plasma concentrations and urinary excretion of carteolol were investigated in 15 patients with varying degrees of renal impairment during the administration of 5–20 mg carteolol hydrochloride (5 mg/tablet) for 2–45 months.Plasma carteolol levels were linearly correlated with the serum creatinine concentration (r = 0.87) and reciprocally with the creatinine clearance (r = 0.82). The urinary carteolol concentration was correlated with the urinary creatinine concentration (r = 0.69) and the urinary carteolol excretion was also correlated with the creatinine clearance (r = 0.79). These relationships become even closer when the plasma carteolol concentrations and urinary excretion rate of carteolol were factored by the administered tablets. The fractional renal excretion of carteolol was virtually constant at various degress of renal function, and it always exceeded 100%, which indicates that carteolol was actively secreted, even in patients with renal failure. The estimated tubular secretion rate of carteolol was logarithmically correlated with the fractional renal excretion of carteolol (r = 0.93).The results indicate that the dose of carteolol should be determined according to the degree of renal impairment.     

Pharmacokinetics of lansoprazole in patients with renal or liver disease of varying severity

Summary The pharmacokinetics of lansoprazole (L) after a single oral dose of 30 mg was determined in 18 healthy volunteers, 17 renal failure patients and 24 hepatic failure patients; 8 hepatitis and 16 with compensated (CC) or uncompensated (UCC) cirrhosis.In renal failure, the absorption of L was unchanged, its half-life being similar to that in healthy subjects; a small change seen in mild renal failure patients (creatinine clearance between 40 and 60 ml/min) was attributed to the age of the patients. Urinary elimination, essentially as metabolites of lansoprazole, was decreased, in relation to the degree of renal impairment.In hepatitis patients, the AUC and t_1/2 of L were doubled, without any change in C_max. In cirrhotics t_max was prolonged, the AUC was increased (P<0.001) and there was prolongation of t_1/2 (6.1 h in CC and 7.2 h in UCC compared to 1.4 h in healthy subjects). These changes resulted from a decrease in the clearance of L. There was also an increase in its sulphone metabolite (C_max, R_m) and a decrease in the hydroxylated metabolite (C_max, R_m) in relation to the degree of liver disease, and reflecting a decrease in hydroxylation and biliary elimination.Thus, renal failure had no effect on the pharmacokinetics of L, but severe hepatic failure caused marked changes. A repeated dosing study would be necessary to evaluate the repercussions of the possible accumulation in cirrhotic patients.     

Drug monitoring of quinine by HPLC in cerebral malaria with acute renal failure treated by haemofiltration

Summary The monitoring of quinine by HPLC in 3 patients suffering from cerebral malaria with acute renal failure and treated by haemofiltration is reported.The recommended dose of quinine in this situation is reduced to 10 to 15 mg·kg^–1·day^–1. However, in the first patient, when given quinine 10 mg kg^–1·day^–1 the plasma concentration was mainly below the recommended therapeutic range of 5 to 15 mg/l. In consequence, the dose of quinine in the second patient was elevated to quinine dihydrochloride 15.1 mg·kg^–1·day^–1 which produced plasma concentrations in the low therapeutic range. In the third patient, an unreduced dose of quinine dihydrochloride 25.7 mg·kg^–1·day^–1 was employed, resulting in plasma concentrations above 15 mg/l, which is generally assumed to be toxic, although, no sign of acute quinine toxicity was seen.The antimalarial effect in all three patients was satisfactory. Quinine was estimated in the haemofiltrate in two patients and was found to be below the limit of sensitivity (0.25 mg/l). Plasma quinine did not change during or shortly after haemofiltration.It is concluded that in case of acute renal failure in cerebral malaria the dose of quinine should be reduced, but that the common recommendation of 10 to 15 mg·kg^–1·day^–1 may be too low, and that haemofiltration has no marked influence on the total body clearance of quinine.     

Pharmacokinetics of tocainide in patients with severe renal failure

Summary The plasma levels of tocainide have been followed after oral administration of 600 mg p.o. to 20 patients with renal failure due to various causes, and to 8 healthy controls. The peak plasma concentrations in the patients with pyelonephritis (3.80 µg/ml) and interstitial nephritis (3.74 µg/ml) but not in those with glomerulonephritis (3.17 µg/ml) differed from that in healthy volunteers (3.24 µg/ml). The renal clearance of tocainide was well correlated with the endogenous creatinine clearance and was dependent on urine pH. No difference in renal clearance was observed between the patients groups. It is suggested that the changes in plasma levels are a consequence of decreased renal clearance. Creatinine clearance was shown to be a poor estimator of tocainide clearance, which suggests that extrarenal clearance plays an important role in the handling of the drug in the body. The findings are used to suggest a safe dosage regimen.     

Pharmacokinetics of acebutolol in patients with all grades of renal failure

Summary The pharmacokinetics of acebutolol was studied in 10 healthy subjects with normal renal function (RN), in 13 patients with various degrees of renal failure (RI) and in 8 patients undergoing repeated haemodialysis (RD). A highly specific method was used to measure acebutolol (A) and N-acetylmetabolite (NAM). In RN the decrease in plasma levels was biexponential with an apparent plasma half lives in the slow phase of A: 8.8±2.3 h and NAM: 11.4±2.2 h. The percentage of the dose excreted unchanged was 13.9% and as NAM 25.8%. Renal clearances were A: 167±20 ml/min and NAM: 150±18 ml/min. The apparent plasma half life of acebutolol does not change according to the degree of renal insufficiency (RI: 7.0±2.7 h, RD: 7.5±2.7 h), while that of NAM is increased (RI: 21.5±10.1 h, RD: 32.3±16.8 h). There is a linear relationship between the apparent elimination rate constant of NAM and creatinine clearance (r=0.832,p<0.001). In RI 21.7% of the dose is excreted in urine (A 5.0%, NAM 16.7%). When renal function is impaired, the renal clearance of A and NAM decrease in parallel with the creatinine clearance (A: r=0.874,p<0.001; NAM: r=0.954,p<0.001). During dialysis the plasma half life fell (A=3.4±0.9 h, NAM=7.4±2.6 h). The dialytic clearance was A: 42.6±12.7 ml/min and NAM: 40.4±16.3 ml/min, for a blood flow of 238±35 ml/min through a dialyser with a cuprophane membrane (Ultraflo II Travenol). Acebutolol is taken up by erythrocytes (_bc=0.50±0.04). The results suggest that the dosage of acebutolol should be adjusted according to the degree of renal insufficiency.     

Lack of interaction of ranitidine with amitriptyline

Summary The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.     

Pharmacokinetics of the loop diuretic piretanide in renal failure

Summary Piretanide 60 mg was administered intravenously over 30 min to 15 men with different degrees of renal failure. The mean piretanide serum concentration at the end of the infusion period was 5.72±1.51 µg/ml. Serum piretanide concentration-time curves declined biexponentially and 24 hours after medication the serum level had fallen to less than twice the detection limit. The terminal half-life ranged from 1.63 to 3.44 h. A relationship to creatinine clearance was not demonstrable. The mean metabolic clearance of piretanide was 107.7±47.6 ml/min/1.73 m² body surface area and was the same as that reported for healthy subjects. The renal clearance of piretanide ranged from 3.33 to 43.9 ml/min/1.73 m² body surface area and very closely correlated with the creatinine clearance (p<0.01). Its renal clearance dependend principally on active secretion of the drug into the tubule, and glomerular filtration appeared unimportant. There was a close relationship between the amount of piretanide excreted in the urine and the creatinine clearance. Because the diuretic effect of piretanide depends on the concentration of the drug in the tubule, the observed correlation might be of use in evaluating the appropriate dosage of piretanide in patients with renal failure. The present data suggest that single daily doses of piretanide will not result in accumulation, even when high doses are administered to patients with advanced renal failure.     

果胶铋对雷尼替丁在人体内药物动力学的影响

目的:研究果胶铋对雷尼替丁的药物动力学的影响.方法:6名健康男性随机分两组交叉单次po雷尼替了胶囊及雷尼替丁和果胶铋胶囊后.采用HPLC测定雷尼替丁的血药浓度,计算药物动力学参数.结果:单用雷尼替丁胶囊和合用果胶铋组T_(1/2β)分别为(1.79±0.32)和(2.04±0.40)h,t_(max)分别为(2.34±0.46)和(2.70±0.49)h,c_(max)分别为(0.93±0.27)和(0.55±0.26)mg/L.AUC_(0-∞)分别为(4.78±1.55)和(3.11±1.57)[(mg/L)·h].经数理统计学分析.两组c_(max)(P0.05).同服果胶铋时雷尼替丁的生物利用度降低约40%.结论:雷尼替丁应尽量避免与果胶铋同时服用.     

Pharmacokinetics of a fixed combination of sotalol and hydrochlorothiazide in hypertensive patients with moderate renal insufficiency

Summary Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.     

Disposition of dibekacin in patients undergoing haemodialysis

Summary The pharmacokinetics of Dibekacin were studied in 10 patients with terminal renal impairment (creatinine clearance <5 ml/min) undergoing haemodialysis sessions lasting 4 h. The dialyzers were either the Gambro Lundia Major 13.5 or the Ultra Flo II 1.4., and the patients were divided into two groups according to the dialyzer used. Blood flow varied between 250 and 280 ml/min and dialyzate flow between 450 and 600 ml/min. All patients received a single i. v. dose of Dibekacin 1.5 mg/kg at the beginning of the dialysis session. The concentration of the antibiotic at the input and the output of the dialyzer were determined microbiologically by a plate diffusion method usingB. subtilis as the test organism. The intravenously administered antibiotic followed an open two-compartment kinetic model. The type of dialyzer used did not influence the dialysis of Dibekacin. Haemodialysis significantly increased the elimination rate of the antibiotic with respect to the interdialysis periods. The plasma half-life in the slow disposition phase fell from 30 h in the interdialysis period to 4.0 h during dialysis sessions. From the calculated pharmacokinetic parameters, a dosage regimen for this kind of patient is proposed.Paper presented at the 8th European Symposium on Clinical Pharmacy, Lyon, France, 24–27 October 1979