Both phenolic and acyl glucuronidation pathways of diflunisal are impaired in liver cirrhosis

Summary The pharmacokinetics of diflunisal, a salicylate derivative that undergoes phenolic and acyl glucuronidation as well as sulphate conjugation, has been studied after a single oral dose (250 mg) in patients with cirrhosis (n=5) and in healthy controls (n=5).The plasma clearance of total (bound + unbound) diflunisal was 10.2 ml · min^–1 in the control subjects and it was not affected by cirrhosis (10.9 ml · min^–1). The plasma protein binding of diflunisal was significantly reduced in cirrhosis; the percentage of unbound diflunisal in plasma was 0.089 in the controls and 0.147 in the patients with cirrhosis. Plasma clearance of unbound diflunisal was significantly impaired in cirrhosis: 11.51 · min^–1 in control subjects vs 7.41 · min^–1 in cirrhotics.In cirrhotic patients, the unbound partial clearances to the phenolic and acyl glucuronides were both significantly reduced, by approximately 38%. The unbound partial clearance to the sulphate conjugate was not significantly affected by cirrhosis.The results show that both the phenolic and acyl glucuronidation pathways of diflunisal are equally susceptible to the effects of liver cirrhosis.     

Oral pharmacokinetics of pirenzepine in patients with chronic renal insufficiency,failure, and maintenance haemodialysis

Summary The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral dose were evaluated in three groups of subjects: group I, end stage renal disease requiring maintenance haemodialysis (CL_CR 0 to 10 ml·min^–1); group II, moderate renal insufficiency (CL_CR 10 to 30 ml·min^–1); and group III, mild renal dysfunction (CL_CR 30 to 70 ml·min^–1). Additionally, subjects in group I received a 50 mg dose on a non-dialysis day and at least one week later, a 50 mg dose during haemodialysis.There was a linear relationship (r = 0.97) between pirenzepine renal clearance and renal function as measured by creatinine clearance. The harmonic mean terminal half-life for pirenzepine was 17.3 h in subjects with end stage renal disease, 18.0 h in subjects with moderate renal insufficiency and 14.7 h in subjects with mild renal dysfunction. Haemodialysis reduced the level of circulating pirenzepine by approximately 25%. The mean arterial to venous plasma pirenzepine ratio during hemodialysis was 1.29 (range 1.02–1.56).Based on subjective reporting of adverse experiences and clinical observation, pirenzepine appeared to have had a wide margin of safety in these patients. Dry mouth was the most frequently reported adverse experience attributable to pirenzepine administration. A reduction in dose or dosing frequency may be warranted only in end state renal disease (CL_CR 0 to 10 ml·min^–1).     

Changes in muscle blood flow after smoking a cigarette determined by a new noninvasive method

Summary The pharmacokinetics of the H₂-receptor antagonist famotidine, after oral administration of a 20 mg tablet, has been studied in 10 elderly patients with normal renal function (CL_CR59 ml·min^–1, Mean=80 ml·min^–1), 5 elderly patients with renal insufficiency (CL_CR38 ml·min^–1, Mean=15 ml·min^–1), and 6 healthy young volunteers.Elimination half-life in the elderly patients with renal insufficiency was significantly prolonged compared to the elderly patients with normal renal function and the young volunteers. The correlation coefficient between creatinine clearance and the elimination rate constant of famotidine was 0.672. Mean urinary recovery of unchanged drug up to 24 h in the young volunteers was 44%. The mean renal clearance of famotidine in the young volunteers (270 ml·min^–1) was substantially greater than the creatinine clearance, 128 ml·min^–1, which suggests the possibility of tubular secretion of famotidine.     

Pharmacokinetics of ciprofloxacin tablets in renal failure; influence of haemodialysis

Summary The pharmacokinetics of ciprofloxacin has been studied after a single oral dose of 500 mg given to 5 normal subjects (N) and to 15 patients grouped according to their residual renal creatinine clearance: Group I, 8–30 ml·min^–1, Group II, <8 ml·min^–1, and Group III, haemodialysed patients studied twice — during an interdialysis period (IIIa) and in a 4 h haemodialysis session (IIIb). Ciprofloxacin was assayed by reverse phase HPLC using a spectrofluorimetric detection. The peak plasma concentration (2–5 mg·l^–1) was reached within 2 h after drug administration. Apparent volume of distribution, 6.6 (N), 5.0 (I), 2.7 (II) and 4.2 (IIIa) l·kg^–1 and total plasma clearance, 770 (N), 440 (I), 378 (II) and 314 (IIIa) ml·min^–1 were decreased in relation to the degree of renal impairment. Mean plasma half-lives for patients in the 4 groups were 7.3 (N), 10.4 (I), 7.2 (II) and 9.3 (IIIa) h. In groups N, I and II, 40, 16 and 8% of the administered dose was eliminated through the kidney, with mean renal clearances of 305±63,61±21 and 21±3 ml·min^–1. A linear relationship was found between the renal clearance of ciprofloxacin and the glomerular filtration rate (r=0.75,n=15). Ciprofloxacin was partly removed by haemodialysis (IIIb): the dialyser extraction ratio was 23% and the dialysis clearance was 40 ml·min^–1.     

Pharmacokinetics and effects of frusemide in patients with the nephrotic syndrome

Summary The renal handling and effects of an intravenous bolus of frusemide with and without plasma volume expansion with dextran or albumin, and with large variations in plasma albumin concentration, have been studied in five patients with the nephrotic syndrome.Decreased renal sensitivity to frusemide was found in only one patient, who also had hypovolaemia and an activated renin-angiotensin-aldosterone system. Plasma volume expansion increased the diuresis but not the saluresis, and slightly increased renal sensitivity to frusemide.An increase in albuminuria after albumin infusion did not reduce the sensitivity to frusemide. A decrease in plasma albumin concentration from 33 g·l^–1 after albumin infusion to 23 g·l^–1 after infusion of dextran caused a substantial increase in the renal clearance (from 84 to 123 ml·min^–1), non-renal clearance (from 72 to 138 ml·min^–1), and apparent volume of distribution (from 13 to 23 l) of frusemide, probably as a consequence of an increase in the unbound fraction. The rate of urinary excretion of frusemide was highest after albumin infusion, despite the fact that its renal clearance was lowest then.     

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.     

Renal clearance of sulphinpyrazone in man

Summary Six healthy young volunteers received a single dose of sulphinpyrazone 200 mg p.o. Plasma concentration and urinary excretion rate curves showed large intersubject variation for sulphinpyrazone and its metabolites. The sulphide metabolite could only be detected in plasma and not before 3–7 h after ingestion. The total recovery in urine of all compounds varied from 30–56% of the dose.In two subjects the mean residence time of sulphinpyrazone was twice as long as in the other subjects (10.4 h compared with 4.6 h), but the area under the plasma concentration-time curve was comparable to that in the others (mean: 3.0 mg·ml^–1·min), indicating that drug absorption was quantitatively similar but delayed.The renal clearance of sulphinpyrazone varied from 14–40 ml·min^–1 (mean: 28 ml·min^–1).In view of the very high plasma protein binding of sulphinpyrazone, active tubular secretion is the predominant mechanism in its renal clearance. The same holds for the sulphone metabolite, which has a mean renal clearance of 24 ml·min^–1, and even more for the p-hydroxysulphinpyrazone metabolite, which has a renal clearance of 118 ml·min^–1.No unambiguous evidence was found in favour of concentration-dependent renal clearance of sulphinpyrazone or its metabolites over the concentration range studied. The renal clearance, especially of sulphinpyrazone, appeared to be dependent on urine pH and not on urine flow rate.     

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated.The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CL_CR<10 ml·min^–1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects.The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance.The maximum target dose in patients with slight renal impairment (CL_CR>30 ml·min^–1) should not be changed. In patients with moderate renal impairment (CL_CR10–30 ml·min^–1) it should be reduced by 50%. In patients with severe renal impairment (CL_CR<10 ml·min^–1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.     

Relationship between renal function and disposition of oral cefixime

Summary The pharmacokinetics of cefixime following a single oral dose of 200 mg have been investigated in 6 normal subjects and in 22 patients with various degrees of renal insufficiency. Serum and urine samples were collected between 0 and 72 h and were subjected to two methods of analysis: bioassay and HPLC.There was a linear relationship between the two sets of results from 228 samples. This result suggests that none of the metabolites, which may accumulte in uraemic patients, has antibacterial activity.In normal subjects, the peak serum level (C_max) was 2.50 g·ml^–1 at 2.83 h (t_max); the apparent elimination half-life (t_1/2) was 3.73 h; the apparent total body clearance (CL·f^–1) was 154 ml·min^–1, the mean renal clearance (CL_R) was 39.1 ml·min^–1 and the apparent fraction of the dose recovered in 24 h urine was 0.22.In uraemic patients, C_max and t_max were slightly increased and t_1/2 was increased to 12–14 h in patients with an endogenous creatinine clearance below 20 ml·min^–1. The apparent volume of distribution was decreased. Apparent total and renal clearances were lower in proportion to the degree of renal insufficiency. Linear relationships were found between CL/f, CL_R and creatinine clearance (CL_CR).The findings suggest that the dose of cefixime needs to be reduced only in patients with severe renal failure.     

Raised plasma levels of atrial natriuretic factor in cardiac allograft recipients: evidence of increased cardiac secretion and decreased renal clearance

The mechanism(s) causing high levels of plasma atrial natriuretic factor (ANF) in cardiac allograft recipients is(are) unclear. The kidney is important for the clearance of ANF and renal function may decline with cyclosporin A therapy in these patients. The relationship between plasma ANF level and renal function and also the pharmacokinetics of a continuous infusion of ANF (15.5 ng·kg^–1·min^–1 for 60 min) was examined in 6 cardiac allograft recipients on cyclosporin A therapy.Resting plasma ANF levels were significantly higher in these patients than in 8 healthy subjects (71 vs. 21 ng·l^–1). Both effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were significantly lower in these patients than in healthy subjects (215 vs. 617 ml·min^–1 and 55 vs. 102 ml·min^–1 respectively). There was a significant inverse correlation between plasma ANF and ERPF (r=-0.86) and between plasma ANF and GFR (r=-0.81). During the period of ANF infusion, steady state plasma ANF levels were significantly higher in cardiac allograft recipients. Total body clearance of ANF was marginally lower in these patients than in healthy subjects (60 vs. 10.0 l·min^–1) although this difference did not reach statistical significance. Derived endogenous secretion rate of ANF was threefold higher in patients when compared to healthy subjects (633 vs. 208 ng·min^–1).We have therefore shown that cardiac allograft recipients on cyclosporin A have elevated plasma ANF levels and also decreased renal function. Pharmacokinetic analysis have shown that this increase in plasma ANF levels is due more to increased ANF secretion than to decreased ANF clearance in these patients.     

Diurnal variation of methotrexate disposition in children with acute leukaemia

Summary There is recent evidence that survival is improved when maintenance therapy for acute lymphocytic leukaemia in children is given at night. We have examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement.In 6 children with leukaemia there was a significant fall in methotrexate plasma clearance at night (from 5.6 to 4.7 ml·kg^–1·min^–1). Renal clearance of methotrexate tended to fall at night and unbound renal clearance fell significantly (from 17.5 to 8.5 ml·min^–1·kg^–1 P<0.05). Creatinine clearance did not exhibit diurnal variation, whereas there was a significant fall in the non-glomerular clearance of methotrexate (from 14.8 to 6 ml·min^–1·kg^–1).Since methotrexate is a weak organic acid, its tubular secretion depends on urinary pH. At night urinary pH is more acidic, and this may result in more reabsorption and hence reduced renal clearance.     

Pharmacokinetics of ranitidine in patients undergoing haemofiltration

Summary The pharmacokinetics of ranitidine was investigated in 11 patients with acute or end stage renal failure during haemofiltration. Each patient received 50 mg ranitidine i.v.The mean distribution and elimination half lives were 0.13 and 2.57 h, respectively. The total body clearance (CL) and volume of distribution (V_z) were 298 ml·min^–1 (5.19 ml·min^–1·kg^–1) and 1.081·kg^–1, respectively. About 17.1% of the administered dose was removed by haemofiltration (in approximately 201 filtrate). Five of the patients still had some urine output and they excreted 0.1 to 11.8% of the dose in urine in 24 h. The haemofiltration clearance was 66.9 ml·min^–1 at a filtrate flow rate of 86 ml·min^–1, corresponding to a mean sieving coefficient of 0.78 (n=6). As plasma concentrations were still in an effective range after haemofiltration, dose supplementation is not recommended.     

The disposition and protein binding of batanopride and its metabolites in subjects with renal impairment

Summary We have studied the disposition of batanopride and its three major metabolites (the erythro-alcohol, threo-alcohol, and N-desethyl metabolites) in 27 subjects with various degrees of renal function after intravenous infusion of a single dose of 3.6·mg·kg^–1 of batanopride over 15 min.The subjects were assigned to one of three treatment groups: group 1, normal renal function (creatinine clearance 75 ml·min^–1·1.73 m^–2; n=13); group 2, moderate renal impairment (creatinine clearance 30–60 ml·min^–1·1.73 m^–2; n=8); group 3, severe renal impairment (creatinine clearance 30 ml·min^–1·1.73 m^–2; n=6).The terminal half-life of batanopride was significantly prolonged from 2.7 h in group 1 to 9.9 h in group 3. The renal clearance of batanopride was significantly lower in group 3 (25 ml·min^–1) compared with group 1 (132 ml·min^–1).There were no differences in plasma protein binding or steady-state volume of distribution of batanopride among the groups.There were significantly lower renal clearances for all three metabolites in groups 2 and 3 compared with group 1. The half-lives of all three metabolites were significantly prolonged in group 3 compared with group 1.The dose of batanopride may need to be reduced in patients with creatinine clearances less than 30 ml·min^–1·1.73 m^–2 to prevent drug accumulation and avoid possible dose-related adverse effects.     

Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal

Summary The single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10–20 cigarettes/day).The plasma clearance of diflunisal was significantly higher in men (0.169 ml·min^–1·kg^–1) and in women on OCS (0.165 ml·min^–1·kg^–1) as compared to control women (0.108 ml·min^–1·kg^–1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml·min^–1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml·min^–1 respectively).Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2–87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.     

The relation between type of renal disease and renal drug clearance in children

Summary It is generally assumed that the renal clearance of drugs in patients with renal impairment are affected to a similar extent regardless of the type of renal disease (intact nephron hypothesis). We have studied the effect of underlying renal disease on the pharmacokinetics of cefotaxime and desacetylcefotaxime in two groups of children (ages 7 to 16 y) with varying degrees of renal dysfunction.Patients in group 1 (n=5) had intrinsic renal disease and those in group 2 (n=5) had extrinsic renal disease, as identified by the primary renal lesion. After a single intravenous dose of cefotaxime timed blood and urine samples were collected for 24 h; cefotaxime and desacetylcefotaxime were measured by HPLC.There were no significant differences between the groups in age, body surface area, urine output, creatinine clearance, total body clearance, nonrenal clearance, renal clearance, and volume of distribution at steady state of cefotaxime, and renal clearance of desacetylcefotaxime. However, the renal clearance: creatinine clearance (CL_R:CL_CR) ratios for both cefotaxime [1.34 in group 1 vs. 0.51 in group 2] and desacetylcefotaxime [1.58 in group 1 vs. 0.75 in group 2] were statistically significant between the two groups. Group 1 patients had an average CL_R:CL_CR ratio greater than 1 for both the parent compound and the metabolite, suggesting that net tubular secretion was still intact, despite a diminished glomerular filtration rate (CL_CR=24 ml·min^–1·1.73 m^–2). In contrast, patients in group 2 (CL_CR=49) ml·min^–1·1.73 m^–2) had an average CL_R:CL_CR ratio less than 1 for both cefotaxime and desacetylcefotaxime, suggesting that renal tubular transport mechanisms did not remain functional in these patients.Our findings suggest that the effect of renal insufficiency on the renal elimination of cefotaxime and its metabolite desacetylcefotaxime may depend on the cause of renal insufficiency.     

Single- and multiple-dose pharmacokinetics of terodiline in geriatric patients

Summary As a target group, geriataric patients were selected for pharmacokinetic studies with terodiline (Mictrol), an anticholinergic and calcium antagonist drug effective in the treatment of urinary incontinence. The single-dose kinetics in the geriatric patients (mean age 82 years) differed significantly from that previously found (Hallén et al. 1987) in healthy volunteers (mean age 35 years). There were higher peak serum concentrations (110 vs 79 µg·l^–1), increased half-life (189 vs 60 h), lower renal clearance (4.0 vs 10.9 ml·min^–1) and lower total clearance (29 vs 75 ml·min^–1). Multiple-doses of 12.5 mg b.d. for 6–8 weeks resulted in a mean steady-state concentration of 642 µg·l^–1, which was in agreement with the single dose parameters. The studied geriatric patients can be characterized not only as old, but also as frail, bedridden, having several diseases and polymedicated. The differences in pharmacokinetics between younger and elderly subjects can be attributed to a variety of complex factors, which may alter the clearance and/or the volume of distribution.     

Furosemide disposition in patients on CAPD

Single doses of oral and intravenous furosemide were given to 8 healthy male volunteers (40 mg) and 11 patients with renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD) (80 mg). In the volunteers, absorption was variable. Only one half of the intravenous dose and one third of the oral dose was available for renal pharmacological action as judged by the urinary recovery. In the patients, absorption was also variable and was markedly delayed (t _max 128 vs 90 min) but more complete (bioavailability 70.1 vs 53.6%). The differences between the two groups were not significant, however (95% C.I.: -90 to 30 and -40.4 to 7.5 respectively). The mean elimination half-life was significantly longer in the patients following both the oral (228 vs 65.1 min) and intravenous dose (195 vs 60.3 min). The total body clearance of furosemide in the volunteers was 138 ml·min^–1 and this was much lower in the CAPD patients (61.9 ml·min^–1) in whom the renal clearance was minimal. The peritoneal clearance of furosemide was negligible. Although there were trends indicating differences in absorption between the two groups, the significant differences in furosemide disposition observed in CAPD patients were due to renal failure.     

Pharmacokinetics of oral acetyl-L-carnitine in renal impairment

Summary Acetyl-L-carnitine 1.5 g and 3.0 g was administered as three divided doses on each of two occasions to 24 people with varying renal failure (creatinine clearance 127 – 8 ml·min^–1). Plasma and urinary concentrations of total-L-carnitine, free (non-esterified) carnitine, short-chain esters and acetyl-L-carnitine were measured.The baseline (pre-study) concentrations of all four substances were related to renal function. Patients whose creatinine clearance was below about 30–40 ml·min^–1 were had the highest concentrations.Renal elimination of all four substances was related to dose and to renal function. There was evidence for dose-related elimination, with greater elimination of the larger dose.     

Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses

The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30–80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (±0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml·min^–1 (±44), plasma protein binding 35% (±6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (±16). Its apparent renal clearance equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.     

Pharmacokinetics of intravenous and oral chlordesmethyldiazepam in patients on regular haemodialysis

Summary The pharmacokinetics of a single 2 mg IV dose of chlordesmethyldiazepam has been studied in 11 patients with renal failure on regular haemodialysis and in 11 age-matched healthy controls. The kinetics was also examined after a single 2 mg oral dose in 6 of the 11 renal failure patients.After intravenous administration the kinetics of total chlordesmethyldiazepam in renal patients and controls were the same. The unbound fraction of the drug in renal patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed a reduced apparent volume of distribution (47 vs. 140 l · kg^–1) and a reduced clearance (5.0 vs. 10.5 ml · min^–1 · kg^–1) in the patients. The systemic availability of oral chlordesmethyldiazepam was good (82%) despite a relatively slow absorption rate.