The effect of renal disease on the pharmacokinetics of diethylcarbamazine in man.

1 The pharmacokinetics of diethylcarbamazine (DEC) were studied in twelve patients with chronic renal function impairment. 2 Selected pharmacokinetic parameters, plasma half-life (T1/2), area under the plasma concentration-time curve (AUC), elimination rate constant (Kel) and 24 h urinary excretion were regressed versus parameters indicative of renal function. 3 Significant negative correlations were observed between creatinine clearance and both plasma T1/2 and log10 T1/2. 4 Significant positive correlations were obtained between (a) creatinine clearance and elimination rate constant of DEC and (b) reciprocal serum creatinine and l/T1/2. Creatinine clearance was significantly and positively correlated with 24 h urinary excretion of DEC. 5 No significant correlations were observed between age, sex or weight and renal function but DEC excretion did appear to decrease with increasing urinary pH. 6 Plasma half-life, and area under the plasma concentration-time curve were increased and 24 h urinary excretion of DEC was significantly reduced in patients with chronic renal function impairment, compared with normal volunteer subjects receiving an identical dosage of DEC at acidic urinary pH.     

Renal safety and pharmacokinetics of ibandronate in multiple myeloma patients with or without impaired renal function

In this open-label study, the authors assessed the pharmacokinetics and safety of ibandronate in patients with multiple myeloma and varying renal function. Renal deterioration was graded at baseline depending on creatinine clearance in 4 stages (0: >80; 1: 50-79; 2: 30-49, and 3: <30 mL/min). Patients (n = 40) received intravenous ibandronate 6 mg (30-minute infusion). Ibandronate excretion and serum levels were measured over 24 hours. Serum creatinine, creatinine clearance, and markers of tubular damage were monitored before ibandronate infusion and at 24 and 72 hours following ibandronate infusion. Ibandronate clearance, AUC(0-24), AUC(0-infinity), serum t((1/2)), and C(max) were calculated. There was a significant positive correlation between ibandronate clearance and creatinine clearance (r = 0.858; P < .00001). The AUC for grade 3 renal insufficiency increased by approximately 60% versus grade 0 (P < .01) but was not significantly different between other grades of renal function. The t((1/2)) did not increase significantly, and peak serum levels of ibandronate were similar for the 4 grades of renal function. Serum creatinine, creatinine clearance, and markers of tubular damage did not change significantly within 72 hours of ibandronate infusion. Despite renal function already being compromised in this patient group, there was no evidence of acute nephrotoxicity with ibandronate.     

Pharmacokinetics of moxifloxacin, a novel 8-methoxy-quinolone, in patients with renal dysfunction

AIMS: To evaluate the influence of impaired renal function on the plasma and urinary pharmacokinetics of moxifloxacin, a novel 8-methoxy-quinolone antibacterial drug. METHODS: Twenty male and 12 female subjects (8 healthy subjects, 24 patients with impaired renal function), 18--75 years of age were investigated in parallel fashion with four groups stratified according to creatinine clearance (CLCR; n=8 for each group). The pharmacokinetics of moxifloxacin and the metabolites M1 (sulphonate metabolite) and M2 (glucuronide) in plasma and urine were determined repeatedly up to 96 h after single oral doses of 400 mg. Patients were monitored intensively with regard to clinical and laboratory safety and tolerability. RESULTS: Single doses of 400 mg moxifloxacin were safe and well tolerated. The urinary excretion of moxifloxacin (Aeur, P: 0.0002) and renal clearance (CLR, P<0.0001) were reduced with decreasing CLCR, mean Cmax was slightly reduced (Cmax-ratio 85.0%, 90% CI 67.9, 106.4% severe renal impairment vs healthy subjects) but the AUC was unchanged even in severe renal impairment (AUC-ratio 101.3%, 90% CI 79.7, 128.6%). The mean AUC of the N-sulphonate M1 was slightly increased (by about 53% for the most severe disease) by impaired renal function, but there was no significant correlation between individual AUC and CLCR, whilst Aeur and CLR were significantly correlated with CLCR. In contrast, for the acylglucuronide M2, Aeur (P: 0.0026), CLR (P<0.0001) and AUC (P: 0.0011) were directly correlated with CLCR. CONCLUSIONS: Renal dysfunction had little effect on the plasma pharmacokinetics of either moxifloxacin or metabolite M1, although their renal clearance and urinary excretion were reduced. In contrast renal dysfunction did result in changes in the plasma pharmacokinetics of metabolite M2, causing greater and longer exposure. However the extent of these changes is unlikely to be of clinical relevance.     

Delayed elimination of triamterene and its active metabolite in chronic renal failure

Summary The kinetics of triamterene and its active phase II metabolite were studied in 32 patients with various degrees of impaired renal function; the creatinine clearances ranged from 135 to 10 ml/min. The area under the plasma concentration-time curves (AUC) for triamterene were not influenced by kidney function, but the AUCs for the effective metabolite OH-TA-ester were significantly elevated in renal failure, indicating accumulation of the metabolite. Urinary recovery of triamterene and its metabolite over a 48 h collection period was significantly reduced in renal failure. This is considered to be due to delayed urinary excretion, corresponding to reduced renal clearance. The renal clearance of the native drug exceeded that of the metabolite, because of their different protein binding, 55% for triamterene and 91% for the metabolite. The latter is eliminated almost exclusively via tubular secretion and extrarenal elimination is less important. Administration of this antikaliuretic is therefore considered hazardous in patients with impaired kidney function.     

The effects of renal function on the disposition of isradipine

The effect of renal function on isradipine kinetics was examined in four groups of subjects (N = 55) who had normal or impaired renal function. Each subject received isradipine orally as a 10-mg capsule. Serial blood samples were obtained from 0 to 48 hours postdose and the isradipine plasma concentrations determined by radioimmunoassay. Kinetic parameters, Cmax, lambda 3, t 1/2, AUC, CL'o (oral clearance), and CLo (oral clearance standardized to body weight) were determined. Marked intersubject variability of the pharmacokinetic parameters was observed. No statistically significant differences (P greater than .05) were found for AUC, Cl'o, and Clo parameters when renal impairment groups were compared with controls. AUC values were lower (P less than .05), however, for the group with severe renal function impairment than for groups with mild or moderate renal function impairment. No significant correlations (r = -.23, P greater than .05; and r = .13, P greater than .05, respectively) were found between creatinine clearance (CLCR) and CLo and between age and CLo. Considering the interpatient variability in isradipine disposition and the lack of significant differences in CLo between groups, no clear-cut dosing regimen alterations, based on single-dose data, are warranted in renal impairment.     

Pharmacokinetics of cerivastatin in renal impairment are predicted by low serum albumin concentration rather than by low creatinine clearance

The influence of renal impairment on the clearance of the new HMG-CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 microg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t 1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax or t 1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.     

Single- and multiple-dose pharmacokinetics, kidney tolerability and plasma protein binding of tenoxicam in renally impaired patients and healthy volunteers

The 20 mg single-dose and 12 days repeated-dose pharmacokinetics of tenoxicam and the 5-OH-tenoxicam metabolite have been evaluated in healthy volunteers and two groups of patients with different degree of renal impairment, in total 20 persons. Concomitantly, the plasma protein binding of tenoxicam and the effects of treatment on renal function were evaluated. No differences were found between the investigated groups in the pharmacokinetics of total tenoxicam and the 5-OH metabolite did not interfere either with the pharmacokinetics or with the plasma protein binding of tenoxicam. A positive correlation was found between an increase in the free fraction (% F) of tenoxicam in plasma and a decrease in the plasma elimination half-life in the low creatinine clearance group (40-20 ml/min.) both after the single-dose and at steady-state. At steady-state, a non-linear correlation was demonstrated between a decrease in the urinary excretion of the 5-OH metabolite and a decrease in creatinine clearance from 130 to 20 ml/min. An increase in the plasma level of the 5-OH metabolite by three times was found in the low creatinine clearance group as compared to healthy subjects. 14C-Impurities of tenoxicam, as low as 1.2%, were shown to greatly influence the determination of the plasma protein binding (equilibrium dialysis) of the highly protein-bound tenoxicam due to a non-binding ability of the impurities to plasma proteins. No significant changes in renal parameters were found during the study. It can be concluded that the pharmacokinetics and plasma protein binding of tenoxicam and the pharmacokinetics of the 5-OH-tenoxicam metabolite are increasingly changed in subjects with a creatinine clearance below 40 ml/min. A decreased binding of tenoxicam to plasma proteins in low clearance patients is probably the reason for a faster elimination of tenoxicam in this group rather than a higher intrinsic hepatic metabolic activity. This study conducted in a low number of patients did not bring forward any new data indicating any adverse effects of tenoxicam on renal function.     

Pharmacokinetics of single-dose reboxetine in volunteers with renal insufficiency

Reboxetine is a new selective norepinephrine reuptake inhibitor (selective NRI) for the short- and long-term treatment of depression that is effective and well tolerated at a dose of 8 to 10 mg/day. This study assessed the pharmacokinetics of reboxetine in volunteers with renal impairment. A single 4 mg dose of reboxetine was administered to a total of 18 volunteers with mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment (creatinine clearance: 56-64, 26-51, and 9-19 ml/min, respectively), and reboxetine concentrations were measured in plasma by HPLC. Mean AUC infinity increased by 43% (mild vs. severe; p < 0.01) as renal function declined, while renal clearance and total urinary excretion of unchanged reboxetine decreased by 67% and 62%, respectively (mild vs. severe; p < 0.01 for both parameters). tmax and t1/2 were not significantly different between groups. In comparison with historical data from young healthy volunteers, AUC infinity and t1/2 are at least doubled in volunteers with renal impairment, while CLr is halved. This pharmacokinetic study has shown that increasing renal dysfunction leads to increasing systemic exposure to reboxetine, particularly in severe renal insufficiency, although reboxetine was well tolerated by all volunteers. Thus, a reduction of the starting dose of reboxetine to 2 mg twice daily would be prudent in patients with renal dysfunction.     

Effects of Long-Term Oral Carvedilol on the Steady-State Pharmacokinetics of Oral Digoxin in Patients With Mild to Moderate Hypertension

The effect of multiple oral doses of carvedilol on steady-state plasma digoxin pharmacokinetics was evaluated in 12 patients with mild to moderate hypertension. Area under the curve (AUC), mean maximum plasma concentration (C_max), mean time to maximum concentration (T_max), concentration at 24 hours after the dose (C₂₄), creatinine clearance, renal digoxin clearance, and urinary digoxin excretion were determined after patients took oral digoxin 0.25 mg once/day for 2 weeks. Carvedilol was added to the regimen, and digoxin pharmacokinetics were assessed after 2 weeks of concurrent treatment. The AUC and C_max for digoxin increased by 14% and 32%, respectively (p<0.05), with no change in T_max. The 24-hour urinary digoxin excretion and 24-hour renal digoxin clearance increased by 45% and 26%, respectively (p<0.05), with no change in creatinine clearance. Carvedilol appears to increase digoxin's oral bioavailability as well as renal elimination. The absolute change in digoxin pharmacokinetics was small and not clinically significant. The significance of the interaction in other patient populations remains to be studied.     

The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in an open study with three parallel groups. Twenty-one patients with severely impaired (ClCr < 25 ml min-1), moderately impaired (ClCr 25-50 ml min-1) and normal (ClCr > 65 ml min-1) renal function were evaluated. A single oral dose of remoxipride hydrochloride 100 mg was administered, and blood and urine were collected over 48 h. Concentrations of remoxipride and metabolites were measured by h.p.l.c. 2. In patients with severely decreased renal function, the AUC and Cmax of remoxipride were increased significantly, and t1/2 was prolonged, as compared with the control patients. The renal clearance and urinary recovery of the unchanged drug were significantly diminished. 3. The unbound fraction of remoxipride in plasma was decreased in patients with renal failure, in association with a disease-related increase in alpha 1-acid glycoprotein. In spite of a 25% recovery of unchanged drug in the urine in patients with normal renal function, the AUC of unbound drug was twice as high in patients with severely impaired renal function. 4. A strong correlation between creatinine clearance and renal drug clearance was observed indicating a direct relationship between kidney function and the renal clearance of remoxipride. 5. Remoxipride was the predominant compound in plasma as well as in urine in patients with severely decreased as well as normal renal function. In patients with severely decrease renal function, remoxipride and all five pharmacologically inactive metabolites showed increased peak plasma concentrations, delayed tmax, increased AUC, prolonged half-lives and decreased renal clearance.     

Effects of short-term treatment with diclofenac-colestyramine on renal function and urinary prostanoid excretion in patients with type-2 diabetes

OBJECTIVE: To determine the effect of short-term administration of diclofenac-colestyramine on glomerular filtration rate (GFR), renal plasma flow (RPF) and urinary excretion of prostanoids in patients with type-2 diabetes without and with impaired renal function.METHODS: In the randomised, single-blind, placebo-controlled, two-period crossover study, 32 patients with type-2 diabetes (group 1: 16 patients without impaired renal function, creatinine clearance > or =80 ml/min and group 2: 16 patients with impaired renal function, creatinine clearance 30-79 ml/min) received 140 mg diclofenac-colestyramine (corresponding to 75 mg diclofenac sodium) or placebo twice a day on days 1 and 2 and once on day 3 with a wash-out period of 6 days between the two periods. GFR was assessed using both measurement of creatinine clearance and calculation of inulin clearance and RPF was assessed using calculation of para-aminohippurate (PAH) clearance after the short-term administration on day 3. Urinary excretion of prostanoids (PGE(2), PGE-M, 6-keto-PGF(1alpha), 2,3-dinor-6-keto-PGF(1alpha), TxB(2), 2,3-dinor-TxB(2) and 11-dehydro-TxB(2)) were measured before and after drug intake.RESULTS: Comparison with placebo showed no effect of diclofenac-colestyramine on creatinine, inulin or PAH clearance ( P>0.05) in patients with type-2 diabetes either without or with impaired renal function. The differences in creatinine, inulin and PAH clearance between the two groups of patients were not influenced by diclofenac-colestyramine. Urinary excretion of PGE(2), PGE-M, 6-keto-PGF(1alpha), 2,3-dinor-6-keto-PGF(1alpha), TxB(2), 2,3-dinor-TxB(2) ( P=1.89) and 11-dehydro-TxB(2) was significantly reduced by diclofenac-colestyramine.CONCLUSION: These results indicate that proven non-specific cyclooxygenase inhibition by short-term administration of diclofenac-colestyramine did not affect renal haemodynamic function (GFR, RPF) in patients with type-2 diabetes either without or with impaired renal function.     

Single‐ and Multiple‐Dose Pharmacokinetics,Kidney Tolerability and Plasma Protein Binding of Tenoxicam in Renally Impaired Patients and Healthy Volunteers

Abstract: The 20 mg single‐dose and 12 days repeated‐dose pharmacokinetics of tenoxicam and the 5‐OH‐tenoxicam metabolite have been evaluated in healthy volunteers and two groups of patients with different degree of renal impairment, in total 20 persons. Concomitantly, the plasma protein binding of tenoxicam and the effects of treatment on renal function were evaluated. No differences were found between the investigated groups in the pharmacokinetics of total tenoxicam and the 5‐OH metabolite did not interfere either with the pharmacokinetics or with the plasma protein binding of tenoxicam. A positive correlation was found between an increase in the free fraction (% F) of tenoxicam in plasma and a decrease in the plasma elimination half‐life in the low creatinine clearance group (40–20 ml/min.) both after the single‐dose and at steady‐state. At steady‐state, a non‐linear correlation was demonstrated between a decrease in the urinary excretion of the 5‐OH metabolite and a decrease in creatinine clearance from 130 to 20 ml/min. An increase in the plasma level of the 5‐OH metabolite by three times was found in the low creatinine clearance group as compared to healthy subjects. ¹⁴C‐Impurities of tenoxicam, as low as 1.2%, were shown to greatly influence the determination of the plasma protein binding (equilibrium dialysis) of the highly protein‐bound tenoxicam due to a non‐binding ability of the impurities to plasma proteins. No significant changes in renal parameters were found during the study. It can be concluded that the pharmacokinetics and plasma protein binding of tenoxicam and the pharmacokinetics of the 5‐OH‐tenoxicam metabolite are increasingly changed in subjects with a creatinine clearance below 40 ml/min. A decreased binding of tenoxicam to plasma proteins in low clearance patients is probably the reason for a faster elimination of tenoxicam in this group rather than a higher intrinsic hepatic metabolic activity. This study conducted in a low number of patients did not bring forward any new data indicating any adverse effects of tenoxicam on renal function.     

The pharmacokinetics of trichlormethiazide in hypertensive patients with normal and compromised renal function

Summary The pharmacokinetics of trichlormethiazide (TCZ) was studied in twelve patients after a single 4 mg dose. Seven patients had normal renal function with creatinine clearances greater than 90 ml/min. Five patients had compromised renal function with creatinine clearances averaging 48±29 ml/min. The TCZ plasma half life and area under the plasma concentration-time curve (AUC) were significantly greater in patients with impaired function, compared to patients with normal renal function. There were no significant differences between the two patient groups in terms of either rate of drug absorption or total urinary recovery of unchanged drug. Furthermore, there was no correlation between peak drug levels or AUC and renal excretion of water or electrolytes.     

Pharmacokinetics of cetamolol in hypertensive patients with normal and compromised renal function

The efficacy, safety, and pharmacokinetic parameters of a 30-mg oral dose of cetamolol hydrochloride (Betacor), a new synthetic cardioselective beta-adrenoceptor antagonist, with intrinsic sympathomimetic activity, were evaluated by studying 32 hypertensive patients with normal renal function or different degrees of renal impairment. After administration of cetamolol, serial blood and urine sample collections, as well as vital sign determinations for the next 48 hours, were performed in all patients (with the exception of urine collection, which was not possible in hemodialysis patients). Results indicate that cetamolol's pharmacokinetic parameters are significantly changed in patients who have moderate or severe renal impairment. Specifically, as the severity of renal impairment increased, the maximum serum concentration (Cmax) and the area under the serum concentration-time curve (AUC) increased, whereas the renal clearance (CLR), urinary excretion, and total body clearance (CL) decreased. Additionally, significant direct or inverse correlations for AUC, CL, CLR, and urinary excretion with creatinine clearance (CLCR) were demonstrated. In the subjects with mild renal impairment, the trends toward changes in the cetamolol pharmacokinetic parameters were evident, though small and not statistically significant. Although anuric, patients on hemodialysis still retained the ability metabolically to clear cetamolol at a rate of about one-third of that found in normal subjects. Reductions in blood pressure and heart rate also were found to be greater and more prolonged as the severity of renal impairment increased. There were no adverse drug or toxic effects noted in any of the study patients. Based on these findings, dosing recommendations are suggested for patients who have compromised renal function because of the effects of renal function on the pharmacokinetics of cetamolol.     

Effect of aging on the pharmacokinetics of acebutolol enantiomers.

Acebutolol (AC) is a chiral beta-blocker that is metabolized to an equipotent chiral metabolite, diacetolol (DC). A stereoselective disposition of AC and DC enantiomers has recently been reported in young healthy subjects. As many physiologic properties affecting drug disposition are progressively altered with increasing age, the effect of aging on the pharmacokinetics of AC and DC enantiomers were investigated in nine subjects ranging from 60 to 75 years after administration of an oral 200-mg dose of racemic AC. Increasing age resulted in a significant prolongation of the elimination t1/2s of R- (r = 0.913) and S-DC (r = 0.811). Also, the S:R ratios of AC urinary excretion (sigma Xu) of enantiomers was significantly correlated with age (r = 0.677). Contribution of declining renal function to age-associated pharmacokinetics changes was subsequently examined. Renal clearance and cumulative urinary excretion of both AC and DC enantiomers were positively correlated with creatinine clearance. In addition, declining creatinine clearance was associated with a subsequent decline in the enantiomer S:R ratio of AC in plasma (AUC S:R, r = 0.807) and urine (sigma Xu S:R r = 0.807). Similarly, a progressive decline in the S:R ratio of DC collected in urine was evident (r = 0.689). Age-related changes in the enantiomers ratios may suggest that an active stereoselective pathway such as renal tubular secretion or nonrenal excretion may be affected in the elderly.     

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)     

Pharmacokinetics of hydrochlorothiazide in relation to renal function

The pharmacokinetics of hydrochlorothiazide (HCT) was investigated in 23 subjects with normal renal function or widely varying degrees of renal failure. The half-life of elimination increased from 6.4 h in subjects with normal renal function to 11.5 h in patients with mild renal impairment (endogenous creatinine clearance between 30 and 90 ml/min), and to 20.7 h in patients with an endogenous creatinine clearance below 30 ml/min. The cumulative urinary excretion and the renal HCT clearance were correspondingly reduced in patients with impaired kidney function. In normal subjects HCT was mainly excreted by tubular secretion, but as renal HCT clearance in patients with renal impairment did not differ significantly from endogenous creatinine clearance, it was concluded that the secretory mechanism is most markedly impaired. In patients with an endogenous creatinine clearance of 30 to 90 ml/min, the dosage of HCT should be reduced to 1/2 and in patients with a endogenous creatinine clearance below 30 ml/min to 1/4 of the normal daily dose to avoid dose dependant side-effects.     

Single-dose pharmacokinetics of felbamate in patients with renal dysfunction

Aims The purpose of this study was to evaluate the effects of renal impairment on the single-dose pharmacokinetics of the antiepileptic felbamate.
Methods Twelve subjects with three levels of renal dysfunction (creatinine clearance >30–80, >10–30 or 5–10  m  min⁻¹ ) and four controls with normal renal function (creatinine clearance >80  ml min⁻¹ were studied). Plasma and urine samples were obtained for 144  h following administration of a single 1200  mg dose.
Results Compared with controls, apparent total body clearance, renal clearance and urinary excretion of felbamate were decreased, and half-life, C _max and AUC values were increased in subjects with renal dysfunction. The magnitude of these changes was associated with the degree of renal dysfunction. Nonrenal clearance and apparent volume of distribution values were also lower in renal dysfunction subjects, but there was no association between the extent of these changes and degree of renal dysfunction. Renal clearance of felbamate accounted for approximately 30% of apparent total body clearance in the control group and from 9–22% in the renal failure patients. Renal clearance of felbamate was significantly correlated with creatinine clearance ( r ²=0.75; P <0.001).
Conclusions These data suggest that initial dosage and titration of felbamate may require adjustment in patients with renal dysfunction.     

The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients.

1. The relationships between renal creatinine clearance and the renal clearances of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were studied in fifteen intensive-care patients who were receiving morphine sulphate by constant intravenous infusion and who had diverse renal function. 2. An arterial blood sample was collected before and after a 4-5 h urine collection. Plasma and urine concentrations of morphine, M3G and M6G were measured by h.p.l.c. Plasma binding of all three compounds in drug-free plasma from healthy volunteers was determined by ultrafiltration. Measured renal creatinine clearance (CLCr,meas) was calculated from plasma and urinary creatinine concentrations (from h.p.l.c.). Also, creatinine clearance was predicted (CLCr,pred) from routine laboratory determination of plasma creatinine (Jaffe method). 3. There were significant linear relationships (P less than 0.001) between CLCr,meas and the renal clearances of morphine, M3G and M6G. The unbound renal clearance of morphine exceeded CLCr,meas (P less than 0.002) while the unbound renal clearances of M3G and M6G did not differ from CLCr,meas (P greater than 0.5). 4. In ten of the patients who received a constant infusion of morphine for at least 6 h, the dose-normalised plasma concentrations of M3G and M6G increased with decreasing CLCr,pred. Significant (P less than 0.001) relationships were observed between the reciprocal of CLCr,pred and the dose-normalised plasma concentrations of M3G and M6G. 5. The results indicate the importance of renal function in determining the renal clearances and plasma concentrations of M3G and M6G during intravenous infusion with morphine in intensive-care patients.     

Organic anion transporter 5 (Oat5) renal expression and urinary excretion in rats treated with cisplatin: a potential biomarker of cisplatin-induced nephrotoxicity

Cisplatin is one of the most potent chemotherapeutic antitumor drugs used in the treatment of a wide range of solid tumors. Its primary dose-limiting side effect is nephrotoxicity. The organic anion transporter 5 (Oat5) is exclusively localized in the kidney. Oat5 urinary excretion was recently proposed as a potential early biomarker of acute kidney injury (AKI). The aim of this study was to evaluate Oat5 renal expression and its urinary excretion in rats exposed to different doses of cisplatin, in comparison with traditional markers of renal injury, like renal histology, creatinine and urea plasma levels, creatinine clearance, protein and glucose urinary levels and urinary alkaline phosphatase (AP) activity. Male Wistar rats were treated with a single injection of cisplatin at different doses of 1, 2, 5 and 10 mg/kg b.w., i.p. (Cis1, Cis2, Cis5 and Cis10, n = 4, respectively) and experiments were carried out 48 h after cisplatin administration. The renal expression of Oat5 was evaluated by immunohistochemistry and Western blotting. Oat5 abundance, AP activity, creatinine, glucose and proteins were assayed in urine. Creatinine clearance and creatinine and urea plasma levels were also evaluated. In this experimental model, plasma urea and creatinine levels, creatinine clearance, AP urinary activity and protein and glucose urinary levels were significantly modified only at the highest cisplatin dose of 10 mg/kg b.w., i.p., as compared to control rats. In contrast, Oat5 urinary abundance was increased in a dose-related manner after the administration of cisplatin. Oat5 urinary abundance was elevated at a dose as low as 1 mg/kg b.w., i.p., implying renal perturbation, when no modifications of traditional markers of renal injury are yet observed. Oat5 renal expression was decreased in a dose-related manner, both in homogenates and apical membranes from cisplatin-treated kidneys. The increase in urinary Oat5 excretion might explain the decrease in the amount of Oat5 molecules in the renal tubule cells. Hence, the preclinical animal results showed in this work propose that Oat5 urinary excretion might potentially serve as a non-invasive early biomarker of cisplatin-induced AKI.