Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis

This single-dose, open-label, parallel-group study compared the pharmacokinetics and tolerability of 120 mg doses of nateglinide, a physiologic mealtime glucose regulator for type 2 diabetes, in 8 subjects with cirrhosis and 8 matched healthy subjects. In both groups, plasma concentration peaked in a median of 0.5 hours, and mean terminal elimination half-lives were comparable. Mean +/- SD pharmacokinetic parameters in cirrhotic versus healthy subjects were slightly different (Cmax, 7.7 +/- 4.9 vs. 5.6 +/- 1.3 micrograms/ml; AUC(0-t), 18.5 +/- 7.5 vs. 14.2 +/- 2.1 micrograms.h/ml, respectively). Mean apparent total clearance and mean renal clearance in both groups were comparable. Mean protein-bound fractions were equivalent; binding appeared unaltered by metabolites. One cirrhotic and 2 healthy subjects each reported one adverse event. No statistically significant or clinically relevant alteration in pharmacokinetic parameters of nateglinide resulted from hepatic dysfunction, and it was well tolerated; therefore, adjustment of nateglinide dosage is not required in subjects with mild to moderate cirrhosis.     

Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status

AIM: To study the pharmacokinetic and metabolism profiles of a single dose of acetaminophen in patients with cirrhosis. METHODS: Oral acetaminophen (1000 mg) was administered to seven healthy subjects and 14 patients with cirrhosis (nine Child-Pugh A or B and five Child-Pugh C grade), being five without and nine with oesophageal varices. Plasma levels of acetaminophen and its metabolites were determined by HPLC. RESULTS: Patients showed a higher mean area under the curve concentration-time (67.4 +/- 22.4 mg h/L vs. 38.8 +/- 4.3 mg h/L; P = 0.01), a lower clearance (166.7 +/- 85.0 mL/min vs. 367.8 +/- 62.5 mL/min; P = 0.01) and higher elimination half-life (3.8 +/- 1.1 h vs. 2.0 +/- 0.4 h; P = 0.01) of acetaminophen than healthy volunteers. The appearance in blood and the urinary excretion of metabolites in patients did not differ from healthy subjects. Absorption profile was faster in patients. Patients with lower mean and systolic arterial pressure had lower AUC of acetaminophen, independently of liver dysfunction stage. CONCLUSIONS: Patients with cirrhosis had a higher AUC and lower clearance of acetaminophen. Acetaminophen attained earlier therapeutic concentrations in patients with oesophageal varices. Mean and systolic arterial pressures were significantly associated with AUC suggesting the importance of the haemodynamic function on the pharmacokinetics of acetaminophen in patients with cirrhosis.     

Pharmacokinetics of molsidomine and its active metabolite, linsidomine, in patients with liver cirrhosis.

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half-life was prolonged in cirrhotic patients (13.1 +/- 10.0 h vs 1.2 +/- 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/- 31.9 ml h-1 kg-1 in patients with cirrhosis vs 590 +/- 73 ml h-1 kg-1 in volunteers). The elimination half-life of the active metabolite, linsidomine (SIN-1) was also prolonged in cirrhotic patients (7.5 +/- 5.4 h vs 1.0 +/- 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine x 100 (4.5 +/- 6.1 in cirrhotic patients vs 23.5 +/- 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.     

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.     

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.     

Liver blood flow, antipyrine clearance, and antipyrine metabolite formation clearance in patients with chronic active hepatitis and alcoholic cirrhosis.

Duplex scanning was used to measure liver blood flow (hepatic artery and main branches of the portal and hepatic veins) in six healthy subjects, five cirrhotic patients, and six hepatitis patients. Antipyrine clearance and formation clearances to its metabolites were also measured. Compared with healthy control subjects, cirrhotic patients had a lower hepatic vein blood flow (-76%, P < 0.05). This was due primarily to a lower portal vein blood flow (-36%, NS). A statistically significant difference in liver blood flow between patients with hepatitis and normal subjects was not detected. Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were significantly different in cirrhotic patients compared with the healthy subjects (mean +/- s.d.-healthy controls: t1/2 = 13.7 +/- 3.0 h, CL = 30.0 +/- 8.6 ml h-1 kg-1, AUC = 549 +/- 139 mg l-1 h; cirrhotic patients: t1/2 = 32.4 +/- 1.7 h, CL = 12.3 +/- 2.1 ml h-1 kg-1, AUC = 1061 +/- 218 mg l-1 h; P < 0.008). Antipyrine half-life, clearance, and the area under the serum drug concentration vs time curve were not significantly different in hepatitis patients compared with the healthy subjects (hepatitis patients: t1/2 = 14.3 +/- 3.7 h, CL = 29.3 +/- 8.5 ml h-1 kg-1, AUC = 498 +/- 142 mg l-1 h). The volume of distribution of antipyrine was similar in all three groups of subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alfentanil-induced miosis as a surrogate measure of alfentanil pharmacokinetics in patients with mild and moderate liver cirrhosis

OBJECTIVES: (i) To evaluate the pupillary response to alfentanil as a surrogate measure of alfentanil pharmacokinetics in cirrhotic patients and to compare the data observed in cirrhotic patients with those found in healthy volunteers (historical control group); and (ii) to compare this test with other liver function tests in cirrhotic patients. METHODS: Six patients with mild cirrhosis (Child-Pugh grade A) and six patients with moderate cirrhosis (Child-Pugh grade B) were studied after a single 15 microg/kg bolus of alfentanil. Alfentanil plasma concentrations were measured by liquid chromatography-tandem mass spectrometry, and pupillary responses were measured with a Pupilscan II pupillometer. Alfentanil pharmacokinetics (plasma concentration, area under the plasma concentration-time curve from time zero to infinity [AUC(infinity(p))] and from time zero to 2 hours [AUC(2(p))], apparent volume of distribution at steady state, clearance and terminal elimination half-life [t((1/2)(p))]) and miosis pseudo-kinetic parameters [AUC(infinity)((miosis)), AUC(2)((miosis)), t((1/2))((miosis))] were determined using a noncompartmental analysis method. In six patients (three Child-Pugh grade A and three Child-Pugh grade B), antipyrine (measure of liver intrinsic activity) and D-sorbitol (measure of liver blood flow) tests were performed. RESULTS: A significant correlation was found between the alfentanil AUC(infinity(p)) and AUC(infinity)((miosis)) (r = 0.6, p < 0.05) in cirrhotic patients. This correlation was even more significant if AUC determinations were limited to the first 2 hours after alfentanil administration (r = 0.9, p < 0.01). Statistically significant differences in pharmacokinetics and miosis pseudo-kinetic parameters were observed between cirrhotic patients and healthy volunteers from our previous experiment (historical control group). The correlations were significant between alfentanil clearance and antipyrine clearance (n = 6, r = 0.9, p < 0.05), alfentanil clearance and steady-state hepatic blood clearance [CL(H(b))] measured by the D-sorbitol test (n = 6, r = 0.9, p < 0.05). CONCLUSION: Alfentanil pharmacokinetic parameters were correlated with miosis pseudo-kinetic parameters in cirrhotic patients. There was a significant decrease in pharmacokinetics and miosis pseudo-kinetics in cirrhotic patients compared with volunteers from the historical control group. Alfentanil-induced miosis has the advantage of being noninvasive and can be limited to miosis measurements during the first 2 hours after alfentanil administration in cirrhotic patients. We thus propose to substitute the AUC(2(miosis)) for alfentanil pharmacokinetics in cirrhosis.     

Binding and disposition of sulfisoxazole in alcoholic cirrhosis

The disposition of sulfisoxazole was studied in six male patients hospitalized with biopsy-proven Laennec's alcoholic cirrhosis and six normal, healthy volunteers. Four of the patients were restudied at a time their liver disease had improved clinically. On the average, compared to the normal group, the metabolism of sulfisoxazole (clearance values with respect to unbound concentration values) appears to be unaltered for the cirrhotic patients. For patients with alcoholic cirrhosis having normal renal function for age and weight, the renal elimination of sulfisoxazole was normal. For those subjects with decreased renal function, the renal clearance of sulfisoxazole appeared to be disproportionately decreased, as evidenced by a lower-than-normal sulfisoxazole renal clearance-to-creatinine clearance values. The apparent steady-state volume of distribution of unbound sulfisoxazole was not altered in cirrhotic patients when compared to normal subjects, while the apparent volume of distribution of total drug increased by more than what could be expected from protein binding changes alone. The elimination rate constant did not differ from values found in normals. These data suggest that the total binding capacity of sulfisoxazole in cirrhotic patients is not different from that of normal subjects.     

Kinetics of intravenous metoclopramide in patients with hepatic cirrhosis

Summary The pharmacokinetics of metoclopramide has been studied after acute IV administration to 12 patients with hepatic cirrhosis (6 with and 6 without ascites) and 6 control subjects.The elimination half-life was significantly longer in patients (11.4 h and 9.9 h in those with and without ascites, respectively, vs 6.4 h in controls). Total plasma clearance was significantly lower in patients (0.29 and 0.36 l·kg^–1·h^–1 vs 0.52 l·kg^–1·h^–1 in controls).The differences between patients with and without ascites did not reach statistical significance. Reduction of functional hepatic blood flow in cirrhotic patients is the probable cause of the observed alteration in metoclopramide kinetics.     

The effects of hepatic impairment on the pharmacokinetics of doxazosin

The pharmacokinetics of doxazosin was determined in an open-label study of 12 male volunteers with hepatic impairment (stable alcoholic cirrhosis) and 12 healthy male volunteers. Participants (fasting) received a single 2 mg doxazosin tablet, and blood samples were collected over a 120-hour period. Safety assessments included laboratory and vital sign (blood pressure, pulse rate, and ECGs) measurements and recording of all reported adverse events. The mean peak plasma concentrations were 10.8 ng/mL and 12.3 ng/mL for the subjects with hepatic impairment and healthy subjects, respectively. The corresponding mean area under the plasma concentration-time curve values were 246 and 172 ng.h/mL, a 43% increase in exposure in the subjects with hepatic impairment (p = 0.02). Although the apparent oral clearance was reduced by 30% in men with hepatic impairment compared with healthy subjects (p = 0.02), the elimination halflife was not significantly changed (24 vs. 22 hours, respectively). Laboratory test results, vital signs, and the incidence of adverse events were similar for the two treatment groups. These findings indicate that the recommended dosing regimen for doxazosin is appropriate for patients with clinically mild to moderate hepatic impairment.     

Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis.

The effect of liver cirrhosis on plasma clearance and metabolite profile of i.v. administered antipyrine was studied in 23 patients with alcoholic liver cirrhosis (age 37-70 years) and 17 healthy subjects (age 28-55 years). Liver volume was also measured and was found to be larger in patients than in controls, mean values being 1.86 and 1.36 l respectively. The elimination half-life of antipyrine in patients with alcoholic liver cirrhosis was significantly longer than in the healthy subjects (P less than 0.001). Mean values were 39.9 and 10.1 h respectively. Alcoholic liver cirrhosis had no effect on the apparent volume of distribution of antipyrine, but antipyrine plasma clearance was substantially reduced in the patients. Mean clearance values (ranges) were 13.5 (9.3-22.8) ml/min in the patients and 49.3 (31.1-103) ml/min in healthy subjects. Normalization of antipyrine plasma clearance for liver volume resulted in an only slightly increased distinction between patients and healthy subjects, mean values (ranges) being 7.8 (3.3-13.0) ml min(-1) 1(-1) and 36.1 (21.9-35.9) ml min(-1) 1(-1) respectively. The cumulative renal excretion of 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was significantly lower in patients with alcoholic liver cirrhosis than in healthy subjects, as was the total recovery of antipyrine and major metabolites from urine. Mean values were 15.0, 8.4 and 41.2% of dose in the patients respectively and 24.3, 25.8 and 68.9% of dose in the control subjects. Excreted amounts of total and unconjugated 3-hydroxymethylantipyrine (HMA) and of unchanged antipyrine were the same in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng.hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Pharmacokinetics and Tolerability of Duloxetine following Oral Administration to Healthy Chinese Subjects

OBJECTIVES: The objectives of the study were to characterise the pharmacokinetics and assess the tolerability of duloxetine in healthy Chinese subjects after single and multiple oral 60 mg dosing. METHODS: This was a single-centre, double-blind, randomised, placebo-controlled, single-period study in healthy native Chinese subjects. A total of 32 subjects, 19 men (14 on duloxetine, 5 on placebo) and 13 women (10 on duloxetine, 3 on placebo) between the ages of 20 and 39 years, participated in the study. Duloxetine 60 mg (enteric-coated pellets in a capsule) was given orally once on day 1 and once daily on days 4 to 9. Sequential blood samples were collected over 72 hours after the dose on days 1 and 9, and a predose sample was obtained on days 7 and 8. Duloxetine concentrations in plasma were determined by a validated liquid chromatography-tandem mass spectrometry method. The tolerability evaluation included a physical examination, vital signs, adverse event monitoring and clinical laboratory evaluations. RESULTS: Duloxetine disposition on oral administration is characterised by a one-compartment pharmacokinetic model. Duloxetine is well absorbed, with a median time of maximum plasma concentration at 6 and 4 hours following single and multiple dosing, respectively. At steady state, the mean apparent oral clearance (CL(ss)/F), mean apparent volume of distribution (V(ss)/F) and mean terminal elimination half-life (t((1/2))) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and V(ss)/F on single dosing were not statistically significantly different (p > 0.05) compared with multiple dosing. The linearity index, calculated as the ratio of the area under the plasma concentration-time curve (AUC) during the dosing interval tau at steady state (AUC(tau)(,ss)) to the AUC from time zero to infinity after single dosing (AUC(infinity,single dose)) was 1.15 (coefficient of variation 35.7%). The accumulation in duloxetine exposure was estimated to be 50% on multiple dosing compared with single dosing, consistent with the t((1/2)) and dosing interval (24 hours). The pharmacokinetic parameters of duloxetine in Chinese subjects were not statistically significantly different from those reported previously in Caucasian and Japanese subjects. There were no clinically significant adverse events, abnormal safety laboratory data or vital sign changes reported. CONCLUSION: Duloxetine pharmacokinetics in healthy Chinese subjects given a 60 mg once-daily dosing regimen were well characterised and consistent with known duloxetine pharmacokinetics in healthy Caucasian and Japanese subjects. Both single dosing and multiple once-daily dosing of duloxetine 60 mg were well tolerated by healthy Chinese subjects in this study.     

Effect of age on the pharmacokinetics of duloxetine in women

AIMS: The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence. METHODS: Twenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentration-time data were analysed by noncompartmental pharmacokinetic methods. Sparse plasma samples were obtained from patients with urinary incontinence treated in two phase II studies: 70 women (24-77 years) who received duloxetine 20 mg day(-1), 30 mg day(-1), or 40 mg day(-1) in Study 2A and 128 women (28-64 years) who received duloxetine 20 mg day(-1), 40 mg day(-1), or 80 mg day(-1) in Study 2B. Based upon the combined data, a model was developed to characterize population pharmacokinetics of duloxetine using the nonlinear mixed-effects modelling program (NONMEM). RESULTS: In Study 1, the elderly (> or = 65 years) exhibited a statistically significant slower elimination rate constant lambdaz compared with younger subjects [elderly-younger difference = -0.022 h(-1)[95% confidence interval (CI) -0.036, -0.008]]. However, no statistically significant differences in either CL/F [elderly-younger difference = -17.4 l h(-1) (95% CI -41.1, 6.23)] or V/F [elderly-younger difference = 115.9 l (95% CI -168.6, 400.4)] were observed. The population pharmacokinetic analysis of Studies 2A and 2B revealed that the CL/F of duloxetine decreased with increasing age. Despite statistical significance, the age effect only accounted for 3% of the interindividual variability in CL/F and unexplained sources of the variation in clearance were still substantial (> 50%). Adverse events were generally mild to moderate, and the incidence of adverse events was generally similar in elderly and non-elderly participants in these studies. CONCLUSIONS: Whereas the results suggest that age has an effect on duloxetine pharmacokinetics, primarily reflected as a slower lambdaz in the elderly, the magnitude of mean changes in CL/F, or V/F was small relative to the large interindividual variation in pharmacokinetics. Elderly participants had a safety profile of duloxetine comparable to their younger counterparts. Specific dose recommendations for duloxetine in the elderly are not warranted.     

Pharmacokinetics of furosemide in patients with hepatic cirrhosis

Summary The pharmacokinetics of furosemide was studied in 7 patients with diagnosed liver cirrhosis and in 7 healthy subjects. Furosemide in plasma and ascitic fluid was analyzed spectrofluorometrically. After a single intravenous dose, the cirrhotic patients showed lower initial plasma concentrations of furosemide because of the larger volume of distribution. The mean half-life in cirrhotic patients was significantly greater than in healthy volunteers. The longer half-life was associated with a reduction in the serum clearance of furosemide. Ascitic fluid volume in the patients ranged from 4.6 to 7.71. There was no significant amount of furosemide in the fluid. The diuretic interchange between this fluid and plasma was slow, as peak concentrations ranged from 0.3 to 0.5 µg/ml within 3 to 5 h after bolus administration of furosemide. Diuresis and urinary sodium excretion, 5 h after furosemide injection, were similar in both groups; larger potassium excretion was found in the cirrhotic patients.     

Binding and disposition of sulfisoxazole in alcoholic cirrhosis

The disposition of sulfisoxazole was studied in six male patients hospitalized with biopsy-proven Laennec's alcoholic cirrhosis and six normal, healthy volunteers. Four of the patients were restudied at a time their liver disease had improved clinically. On the average, compared to the normal group, the metabolism of sulfisoxazole (clearance values with respect to unbound concentration values) appears to be unaltered for the cirrhotic patients. For patients with alcoholic cirrhosis having normal renal function for age and weight, the renal elimination of sulfisoxazole was normal For those subjects with decreased renal function, the renal clearance of sulfisoxazole appeared to be disproportionately decreased, as evidenced by a lower-than-normal sulfisoxazole renal clearance-to-creatinine clearance values. The apparent steady-state volume of distribution of unbound sulfisoxazole was not altered in cirrhotic patients when compared to normal subjects, while the apparent volume of distribution of total drug increased by more than what could be expected from protein binding changes alone. The elimination rate constant did not differ from values found in normals. These data suggest that the total binding capacity of sulfisoxazole in cirrhotic patients is not different from that of normal subjects.Supported in part by Grants GM 25807, GM 28423, HL-11046 and AM-06415 from National Institutes of Health.     

Influence of age,renal and liver impairment on the pharmacokinetics of risperidone in man

The pharmacokinetics of the antipsychotic agent risperidone were investigated in healthy young and elderly subjects, cirrhotic patients and patients with moderate and severe renal insufficiency. In a comparative trial, a single oral 1-mg dose was administered to fasting subjects. Plasma and urine concentrations of the parent compound risperidone and the active moiety (i.e. risperidone plus 9-hydroxy-risperidone) were measured by radioimmunoassays. No or only small changes in plasma protein binding were observed in hepatic and renal disease, whereas the protein binding was not influenced by aging. The inter-individual variability in plasma concentrations of the active moiety was much less than the variability in plasma concentrations of risperidone. Three out of six subjects, behaving like poor metabolizers, were on medication (thiethylperazine, amitriptyline, metoprolol) that may inhibit risperidone metabolism by CYP2D6 (debrisoquine 4-hydroxylase). The pharmacokinetics of risperidone in elderly and cirrhotic patients were comparable to those in young subjects, whereas total oral clearance was reduced in renal disease patients. The elimination rate and clearance of 9-hydroxy-risperidone was reduced in elderly and renal disease patients because of a diminished creatinine clearance. The CL_oral of the active moiety, which is primarily 9-hydroxy-risperidone, was reduced by about 30% in the elderly and by about 50% in renal disease patients. In addition, the t_1/2 of the active moiety was prolonged (19 h in young subjects versus about 25 h in elderly and renal disease patients). Based upon the pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration is advised in the elderly and in patients with renal disease. In cirrhotic patients, the single-dose pharmacokinetics were comparable to those in healthy young subjects.     

The metabolism and bioavailability of morphine in patients with severe liver cirrhosis.

1. The oral and intravenous kinetics of morphine were investigated in seven cirrhotic patients with a history of encephalopathy. The plasma concentrations of morphine and its metabolites morphine-3 (M3G) and morphine-6 (M6G) were measured by h.p.l.c. 2. The mean terminal elimination half-life of morphine was 4.2 h (95% CI 3.6-4.8) the mean volume of distribution was 4.1 l kg-1 (95% CI 2.9-5.4) and the mean plasma clearance was 11.4 ml min-1 kg-1 (95% CI 8.1-14.7). The mean oral bioavailability was 101% (95% CI 56-147). 3. The plasma clearance of morphine was significantly lower, its terminal elimination half-life longer and its oral bioavailability greater in the cirrhotic patients compared with patients with normal liver function. The metabolic ratio M3G/morphine was significantly lower in the cirrhotic patients than in control subjects after oral dosing, but did not differ after intravenous dosing. 4. The average urinary recoveries of morphine plus M3G and M6G were 49.9% after i.v. and 57.7% after oral administration. There were no statistically significant differences in the urinary recovery between the two routes of administration or between the cirrhotic patients and controls. 5. Specific changes in the EEG pattern could not be detected after intravenous dosage. 6. The metabolism of morphine is impaired significantly in patients with severe cirrhosis. Clinically important findings were a high oral bioavailability and a long elimination half-life. These findings call for cautious dosing of oral and intravenous morphine in patients with severe end stage liver disease.