Clofibrate disposition in renal failure and acute and chronic liver disease

Summary The disposition of clofibrate over 96 hours was observed following single oral dose in six patients with acute viral hepatitis, six patients with liver cirrhosis, seven patients with renal insufficiency, and six control subjects. No parameter of the disposition of CPIB (active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the non-protein bound drug was reduced (115 vs. 243 ml×min^–1), plasma protein binding was reduced (92.8 vs. 97.2 percent), and the apparent volume of distribution was increased (0.20 vs. 0.141×kg^–1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml×min^–1) and plasma clearance of the unbound drug (81 vs. 243 ml×min^–1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.     

Cirrhosis of the liver markedly impairs the elimination of mexiletine

Summary To study the effects of cirrhosis of the liver on the pharmacokinetics of mexiletine a single i.v. dose of 200 mg was administered to six cirrhotic patients and to six healthy controls. The distribution of mexiletine in both study groups was similar, as indicated by similar values of V₁ and V_ss, but it tended to occur more slowly in the cirrhotics. The plasma protein binding of mexiletine was unchanged in the patients with cirrhosis. The elimination of mexiletine was markedly retarded in the cirrhotics, as indicated by its lower total clearance (2.31 vs. 8.27 ml/kg/h,) lower total elimination rate constant (0.059 vs 0.353 h^–1), and longer elimination half-life (28.7 vs 9.9 h). The antipyrine half-life was 38.3 h in the patients and 14.7 h in the controls. One healthy volunteer had a Morgagni-Stokes-Adams type of syncopal attack 5 min after administration of mexiletine due to disturbance of AV conduction induced by the drug. Thus, on a pharmacokinetic basis the loading dose of mexiletine need not be modified in cirrhotic patients, whereas the maintenance dosage should be reduced to one fourth — one third of the usual dose.     

Alprazolam kinetics in patients with renal insufficiency

Alprazolam kinetics following a single 1.0-mg oral dose of alprazolam were compared between seven dialysis-dependent patients with chronic renal failure and seven healthy controls matched for age, sex, and weight. There were no significant differences between patients and controls in alprazolam half-life (11.5 vs. 11.3 hours) or clearance of total drug (1.14 vs. 1.26 ml/min/kg). However, alprazolam free fraction was increased in renal failure patients (35.7% vs. 31.9% unbound, p less than 0.005). Free clearance of alprazolam averaged 23% lower in patients (3.2 vs. 4.1 ml/min/kg), but the difference was not significant. Renal insufficiency has a quantitatively small influence on alprazolam pharmacokinetics.     

Pharmacokinetics of cimetidine in advanced cirrhosis

Summary The effect of impaired liver function on the pharmacokinetics of cimetidine was studied in 8 patients with advanced cirrhosis given single doses of 100 mg i.v. and 400 mg p.o. on separate days. Compared to a control group of 10 healthy volunteers, the total renal and nonrenal clearance was significantly reduced in the cirrhotic patients; (total plasma clearance mean ± SD) 356±181 vs 789±262 ml/min (p<0.01); renal clearance (Cl_r) 296±100 vs 588±181 ml/min (p<0.01) and nonrenal clearance (Cl_nr) 97±111 vs 205±89 ml/min (p<0.05). Compared to published results for age-matched ulcer patients, both total and nonrenal clearance were lower whereas renal clearance was within the reported normal range. A significant reduction in volume of distribution (V_d) was found, from 2.1±0.1 l/kg in controls to 1.0±0.4l/kg, and in the patient group there was a significant correlation between V_d and total plasma clearance (r=0.72, p<0.05). Volume of distribution in steady state (V_dss) did not differ from published results in age-matched controls. No significant change in half-life was found. Bioavailability, estimated by AUC-measurement, showed considerable patient variability (21–143%), with a mean of 70±39%. This was lower than in the controls. In contrast, measurement of urinary excretion showed higher bioavailability in the patients (66±23 vs 51±8%). No correlation was found between any of the kinetic parameters and the clinical and laboratory data. It is suggested that patients with advanced cirrhosis should be closely observed when given cimetidine, and a reduction in dose should be concidered if side effects are to be avoided.Part of this study has been reported as a Letter to the Editor, N Engl J Med (1982): 307, 187     

Pharmacokinetics of enprofylline in patients with impaired renal function after a single intravenous dose

Summary Enprofylline, a new bronchodilating drug, was given i.v. at 1.0 mg/kg to 7 healthy subjects and to 14 patients with differing degrees of chronic renal insufficiency. Plasma and urine concentrations of unchanged drug were followed by HPLC. In the patients the plasma half-life was prolonged and the total and renal clearances were reduced in direct proportion to the degree of renal insufficiency as determined by creatinine clearance. The unbound fraction of enprofylline in plasma increased from 55% in the healthy subjects to 66% in the group of patients with the highest degree of renal impairment. The volume of distribution terms, V and V_ss, both tended to decrease with decreasing creatinine clearance. When the volume term calculations were based on the unbound drug level in plasma, this tendency was enhanced. Side-effects were noted in 4 subjects, and to some extent were related to the plasma level of the drug.     

Effects of probenecid on enprofylline kinetics in man

Summary Enprofylline 1 mg/kg, a new potent antiasthmatic xanthine derivative, which is mainly eliminated by renal excretion, was given intravenously to 6 normal subjects with and without oral pretreatment with 1 g probenecid. The latter caused a drop in the average total body clearance of enprofylline from 21 to 9.8 l/h, and in the average renal clearance from 17 to 8.0 l/h. The average half-life increased from 1.8 to 3.0 h. The volumes of distribution, V_z and V_ss, both fell by about 25%, indicating that probenecid had restricted the distribution of enprofylline in the body. The plasma protein binding of enprofylline was not altered by probenecid. The results confirm the opinion that active tubular secretion accounts for a large proportion of the total elimination of enprofylline.     

Pharmacokinetics of intravenous bisoprolol in obese and non-obese volunteers

Summary The pharmacokinetics of a single i. v. dose of dlbisoprolol 0.16 mg·kg^–1 ideal body weight has been studied in 8 obese women (mean weight 91 kg; 161% of ideal body weight) and 8 non-obese women (51 kg; 94% of ideal body weight).Compared to the controls, the obese subjects showed an increase in the total apparent volume of distribution (V_z) (182 vs 135 1) and a decrease in V_z per kg body weight (2 vs 2.7 l·kg^–1). There was a negative correlation between V_z l·kg^–1 and the percentage of ideal body weight (r=–0.672). Total body clearance was increased, but t_1/2 and renal clearance was unchanged.It is concluded that tissue diffusion of bisoprolol in obese subjects is limited, despite its lipophilicity, possibly because of alteration in the blood flow to adipose tissue produced by bisoprolol.     

Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects

To study the effects of cirrhosis of the liver on the pharmacokinetics of midazolam single IV (7.5 mg as base) and p.o. (15.0 mg as base) doses of midazolam were administered to seven patients with cirrhosis of the liver and to seven healthy control subjects. One cirrhotic patient did not receive the oral dose. The distribution of midazolam in both study groups was alike as indicated by similar values of t1/2 alpha, V1 and Vss. Also the plasma protein binding of midazolam was unchanged in the patients with cirrhosis. The elimination of midazolam was significantly retarded in the patients as indicated by its lower total clearance (3.34 vs. 5.63 ml/min/kg), lower total elimination rate constant (0.400 vs. 0.721 h-1), and longer elimination half-life (7.36 vs. 3.80 h). The bioavailability of oral midazolam was significantly (P less than 0.05) higher in patients than controls (76% vs. 38%). The antipyrine-half-life was 32.4 h in the patients and 11.8 h in the controls. There were statistically significant (P less than 0.01) correlations between the clearances of the two drugs (r = 0.680) and between their half-lives (r = 0.755). The hypnotic effects of midazolam were similar in both groups. However, on a pharmacokinetic basis a reduced dosage of midazolam to patients with advanced cirrhosis of the liver is recommended.     

Femoxetine Clearance in Patients with Liver Cirrhosis

Abstract: The pharmacokinetics of femoxetine (a 5-HT uptake inhibitor with antidepressive effect) was studied in 12 patients with üver cirrhosis and in 6 healthy controls after a single oral dose of femoxetine HC1. The average blood concentration of femoxetine, as assessed by the values of AUC (area under the plasma concentration/time curve), was significantly higher in the patients with liver cirrhosis than in the healthy controls in spite of dose reduction in the patients. The elimination half-life of femoxetine was within the normal limits in most of the patients. The oral clearance of femoxetine was considerably lower in patients, (0.65–4.02 1/hr/kg) than in the controls (8.13->50 1/hr/kg). It was not directly related to the metabolic function of the liver, measured as the galactose elimination capacity being 0.015–0.024 mmol/min./kg and 0.033–0.041 mmol/min./kg, respectively. When treating patients with reduced liver function, it is recommended to reduce the doses and to monitor closely the plasma levels     

Diazepam kinetics in patients with renal insufficiency or hyperthyroidism.

1 Eight patients with end-stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half-life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min-1 kg-1, P less than 0.01). 3 However, differences were largely related to disease-related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min-1 kg-1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End-stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.     

The effect of piperacillin dose on elimination kinetics in renal impairment

Summary The effect of drug dose on piperacillin elimination kinetics was examined in 27 adult subjects with varying renal function. Piperacillin, 15 mg/kg or 60 mg/kg, was given by bolus intravenous injection. The elimination half-life (t_1/2) increased five-fold and plasma clearance (Cl_p) decreased by 80% in patients with renal failure. Both parameters were dose dependent in patients with normal renal function, but not in patients with renal insufficiency. Piperacillin dose dependent elimination is due primarily to capacity limited renal excretion.     

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.     

Effects of age and chronic renal failure on the urinary excretion kinetics of famotidine in man

Summary The plasma and urine concentrations of famotidine, a new, potent H₂-receptor antagonist, have been measured in 16 healthy young adults, 8 healthy elderly people and 18 patients with varying degrees of renal dysfunction after intravenous administration.Both the plasma elimination and renal excretion of famotidine were decreased in the elderly volunteers and renal patients. The renal clearance of famotidine averaged 4.43 ml/min/kg (310 ml/min) in normal young volunteers, which exceeded the mean creatinine clearance 1.55 ml/min/kg (109 ml/min), suggesting net secretion is a significant mechanism for elimination of famotidine.The ratio of famotidine renal clearance to creatinine clearance decreased as creatinine clearance decreased; these results suggest that the deterioration in the secretion process was much faster than that in glomerular filtration and are incompatible with the intact nephron hypothesis. Nevertheless, both total body clearance and renal clearance were significantly correlated with creatinine clearance.The apparent half-life was also significantly correlated with creatinine clearance. Since famotidine is essentially free of dose-related adverse effects, dose adjustment in patients with mild renal insufficiency and in elderly people is not required; however, either a prolonged dosing interval or a decrease in daily dose during long-term therapy may be adapted for the patients with severe renal insufficiency to avoid accumulation and the potential undesirable effects.     

Disposition of guanadrel in subjects with normal and impaired renal function

The disposition of a single 25 mg oral dose of guanadrel was evaluated in 22 subjects with various degrees of renal function. The terminal elimination half-life was significantly prolonged in subjects with a creatinine clearance (ClCr) less than 30 mL/min/1.73 m2 (19.2 +/- 16.8 h) compared to 3.7 +/- 1.9 h in subjects with a ClCr greater than 80 mL/min/1.73 m2. Apparent total body clearance (Clp/F) was also progressively lower in the patients with decreased renal function and the decline was significantly correlated with ClCr (Clp/F = 0.0294 + 0.0236 Clcr, r = 0.74, P = 0.002). Renal clearance and apparent nonrenal clearance also declined as creatinine clearance decreased, and both were significantly correlated with the observed ClCr. Apparent volume of distribution averaged 11.5 +/- 8.9 L/kg and did not differ in patients with decreased renal function compared to those with normal renal function. Thus, the disposition of guanadrel is significantly altered in the presence of renal insufficiency and dosage adjustments may be necessary, especially in patients with ClCr less than 50 ml/min.     

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.     

Clinical pharmacokinetics of famotidine.

Famotidine is a potent histamine H2-receptor antagonist widely used in the treatment and prevention of peptic ulcer disease. After intravenous administration the plasma famotidine concentration-time profile exhibits a biexponential decay, with a distribution half-life of about 0.18 to 0.5h and an elimination half-life of about 2 to 4h. The volume of distribution of the drug at steady-state ranges from 1.0 to 1.3 L/kg; plasma protein binding is low (15 to 22%). Famotidine is 70% eliminated unchanged into urine after intravenous administration. The total body and renal clearances of famotidine correlate significantly with creatinine clearance. Because its renal clearance (15 L/h) far exceeds the glomerular filtration rate, famotidine is considered to be eliminated not only via glomerular filtration but also via renal tubular secretion. Since its clearance is reduced in patients with renal insufficiency and in elderly patients, the maintenance dosage should be reduced in these patient groups. Removal of famotidine by any of the currently employed blood purification procedures (haemodialysis, peritoneal dialysis and haemofiltration) does not occur to a clinically significant degree. Liver cirrhosis does not appear to affect the disposition of famotidine unless severe renal insufficiency coexists. After oral administration, peak plasma concentrations are attained within 2 to 4h; the oral bioavailability ranges from 40 to 50%, due mainly to incomplete absorption. The oral absorption of the drug is dose-independent within a range of 5 to 40 mg. There are 3 formulations available (tablet, capsule and suspension), which appear to be bioequivalent. Coadministration of potent antacids reduces the oral absorption of famotidine by 20 to 30%. On a weight-to-weight basis, the antisecretory effect of famotidine is about 20 and 7.5 times more potent than those of cimetidine and ranitidine, respectively. Plasma famotidine concentrations correlate with its antisecretory effect: values of about 13 and 20 micrograms/L produce a 50% reduction in the gastrin-stimulated gastric acid secretion and a fasting intragastric pH of greater than 4, respectively. Available data suggest that famotidine interacts neither with the hepatic oxidative drug metabolism nor with the tubular secretion of other commonly used therapeutic agents. However, further studies are required to evaluate a full spectrum of its drug interaction potential.     

Influence of renal insufficiency on the pharmacokinetics of cicletanine and its effects on the urinary excretion of electrolytes and prostanoids.

1. The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2. In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half-life established around 7 h, and both its renal clearance (0.4 ml min-1) and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half-life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3. Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration-effects curves but reduced the maximum effect observed for water, sodium and potassium. 4. A single oral dose of cicletanine did not change the urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of renal insufficiency and haemodialysis on the kinetics of ciprofibrate.

1. The kinetics of the hypolipidaemic drug, ciprofibrate, were studied after a single oral dose (100 mg) in subjects with normal renal function (n = 6), patients with mild (n = 6) and severe (n = 6) renal insufficiency as well as in haemodialysed patients (n = 5). 2. Under fasting conditions, ciprofibrate, was absorbed rapidly in subjects with normal renal function, and its apparent elimination half-life was approximately 81 h. Both renal clearance (0.15 ml min-1) and cumulative renal excretion (less than 7% of the administered dose) were low. 3. Mild renal insufficiency did not alter the pharmacokinetics of ciprofibrate, but severe renal impairment significantly reduced both its renal clearance and cumulative urinary excretion and increased the apparent elimination half-life. 4. A 5 h haemodialysis session did not lower the plasma concentrations of ciprofibrate. 5. It is concluded that, from a pharmacokinetic point of view, a reduction in the dosage of ciprofibrate should be considered in patients with a glomerular filtration rate below 30 ml min-1/1.73 m2.     

Reduced distribution and clearance of acetaminophen in patients with congestive heart failure

Acetaminophen is a widely prescribed analgesic/antipyretic metabolized by hepatic glucuronide and sulfate conjugation. Twelve patients, 30-66 years of age, with stable Class III or IV congestive heart failure (CHF) and 12 healthy controls matched for age, sex, and weight received single 650-mg intravenous doses of acetaminophen. Pharmacokinetic variables were determined from multiple plasma acetaminophen concentrations measured by liquid chromatography during 12 h after the dose. Compared with controls, mean total clearance of acetaminophen was reduced in CHF patients (3.56 vs. 4.59 ml/min/kg, p less than 0.025), indicating reduced biotransformation capacity in this disease. Volume of distribution was also significantly reduced in CHF patients (0.85 vs. 1.02 L/kg, p less than 0.05). Since elimination half-life depends on both volume of distribution and clearance (both of which were reduced), the half-life was similar between groups (2.87 vs. 2.34 h, NS). Thus, hepatic conjugation of acetaminophen is impaired in CHF. The finding may also apply to other drugs biotransformed by conjugation.