The effect of nisoldipine on apparent liver blood flow and effective renal plasma flow.

The effects of the acute and continued administration of the calcium antagonist nisoldipine on hepatic and renal blood flow and on renal function were studied in nine normotensive volunteers. There were no significant changes in supine blood pressure or heart rate but acute administration significantly increased both apparent liver blood flow and effective renal plasma flow. With continued administration these increases were attenuated and were not significantly different from placebo after 4 days treatment. Acute nisoldipine administration was also associated with significant increases in glomerular filtration rate and urinary sodium excretion.     

Altered hepatic blood flow and drug disposition.

For some drugs, delivery to the liver by the hepatic circulation is an important determinant of removal by this organ. Classical pharmacokinetic analyses cannot predict the changes produced by altering any of the biological determinants of drug elimination by the liver; hepatic blood flow, metabolic enzyme activity, drug binding and route of administration. However, with the use of a physiological model of hepatic drug elimination, such predictions can be made. This model has been tested experimentally and appears to be valid. Hepatic blood flow can vary over about a 4-fold range from half normal flow to twice logical changes affecting the circulation. For drug clearance to be affected significantly by these changes in flow, the drug must be avidly removed by the liver as reflected in a high hepatic extraction ratio and intrinsic hepatic clearance. This latter term is a useful way to characterise the ability of the liver to irreversibly remove drug from the circulation in the absence of any flow limitation. The clearance of drugs with low intrinsic clearance will not be affected significantly by changes in liver blood flow.     

Verapamil in antihypertensive treatment of patients on renal replacement therapy — clinical implications and pharmacokinetics

Summary Twenty-eight hypertensive patients on renal replacement therapy (HD, HF, PD) were treated with verapamil (Isoptin RR-slow release) in an open label study. Blood pressure was satisfactorily reduced in 21 patients (84%). Due to adverse reactions the treatment had to be discontinued in 4 patients. Verapamil clearances were calculated according to different dialysis methods. No changes in dose or mode of application of verapamil were necessary using any mode of renal replacement therapy.     

The pharmacokinetics and pharmacodynamics of the diuretic bumetanide in hepatic and renal disease.

1 Bumetanide (1 mg) was given orally and intravenously to a group of patients with chronic renal failure (n = 6) and to another group with cirrhosis of the liver (n = 8). 2 The pharmacokinetics, using a two-compartment model, and the pharmacodynamics of the drug in these patients were compared with those previously obtained for normal subjects. 3 In the renal group serum bumetanide concentrations were higher than for the normal subjects and the terminal half-lives were significantly prolonged (P less than 0.001). A decreased whole body clearance was attributable to a low renal clearance of drug, the non-renal clearance being significantly increased (P less than 0.01). 4 For the patients with liver disease, serum bumetanide concentrations were higher than for the renal group, and the terminal half-lives were significantly further prolonged (P less than 0.001). Both non-renal and renal clearances were significantly reduced (P less than 0.001). 5 Absorption rates were not significantly altered in either group and the values of F (bioavailability) were 0.82 and 0.95 for the patients with renal disease and hepatic disease, respectively. 6 A poor pharmacodynamic response and a reduced bumetanide excretion rate were observed for the patients with chronic renal failure, whereas with hepatic disease normal bumetanide excretion rates were observed with an impaired diuretic response.     

Verapamil pharmacokinetics and liver function in patients with cirrhosis

In seven patients with liver cirrhosis, verapamil plasma levels were measured in blood drawn simultaneously from the hepatic vein and from an artery during the post-distributive phase after an intravenous bolus infusion of 5 mg of verapamil. In addition the hepatic plasma flow was measured using the indocyanine-green constant infusion technique. From these data the verapamil hepatic clearance and verapamil intrinsic clearance were calculated. The verapamil hepatic clearance was 423 +/- 92 ml/m, the hepatic plasma flow was 819 +/- 318 ml/m, and the verapamil intrinsic clearance was 1431 +/- 961 ml/m. As compared to values reported in the literature, a decrease of the verapamil hepatic clearance by 50% approximately was found, while the hepatic plasma flow was in the normal range and the verapamil intrinsic clearance was reduced by 75%. These data show that in patients with cirrhosis the decrease in verapamil clearance is due to an impairment in the capacity of the liver to remove the drug, and not to a decrease in liver perfusion.     

Physiological and pharmacological variability in estimated hepatic blood flow in man.

1 Changes in hepatic blood flow have been estimated by measurement of single-dose indocyanine green kinetics in groups of healthy individuals. 2 The effects of change in posture, exercise and ingestion of milk on estimated hepatic blood flow have been assessed. 3 The erect posture and exercise significantly decreased ICG clearance. However, no consistent change was noted after ingestion of milk. 4 The effects of the adrenoceptor blocking drugs phenoxybenzamine, propranolol and labetalol on hepatic blood flow were also assessed. 5 Propranolol and labetalol caused a significant fall in ICG clearance in the supine position. Phenoxybenzamine did not show a consistent change. 6 Posture, exercise and adrenoceptor blockade appear to be important variables affecting hepatic blood flow. They should be considered when kinetics of high-clearance drugs are measured, and may provide a useful model for the assessment of the effects of alterations in hepatic blood flow on the clearance of drugs.     

The influence of captopril, the nitrates and propranolol on apparent liver blood flow.

Indocyanine green estimated apparent liver blood flow was measured in normal volunteers following glyceryl trinitrate, propranolol, isosorbide mononitrate and captopril. Glyceryl trinitrate and propranolol significantly reduced apparent liver blood flow. Isosorbide mononitrate did not alter apparent liver blood flow or produce an additional reduction in apparent liver blood flow when combined with propranolol. Captopril did not alter apparent liver blood flow despite a significant fall in mean arterial pressure and rise in plasma renin activity. Captopril and isosorbide mononitrate if shown to reduce portal pressure, do so without a fall in apparent liver blood flow.     

Effects of hepatic or renal impairment on the pharmacokinetics of aripiprazole

BACKGROUND AND OBJECTIVES: Two studies were conducted to investigate whether the pharmacokinetics of the atypical antipsychotic aripiprazole were altered in individuals with hepatic or renal impairment compared with those with normal hepatic or renal function. STUDY DESIGN: Two open-label, single-dose studies. STUDY SETTING: Clinical research unit. PATIENTS: Study 1: Subjects with normal hepatic function (n = 6) and subjects with hepatic impairment (Child-Pugh class A [mild, n = 8], B [moderate, n = 8] or C [severe, n = 3]). Study 2: Subjects with normal renal function (creatinine clearance >80 mL/min; n = 7) and subjects with severe renal impairment (creatinine clearance <30 mL/min; n = 6). TREATMENT: Single oral dose of aripiprazole 15 mg. PHARMACOKINETIC ANALYSES: Noncompartmental pharmacokinetic analysis was performed using plasma aripiprazole and dehydro-aripiprazole concentration-time data. MAIN OUTCOME MEASURES: Study 1 (hepatic impairment study): apparent oral clearance of unbound drug (CL/Fu) and the maximum plasma concentration (Cmax) of aripiprazole; Study 2 (renal impairment study): CL/Fu, Cmax and renal clearance (CL(R)). Safety assessments included 12-lead ECGs, vital sign monitoring, clinical laboratory measurements and assessment of adverse events.f RESULTS: In the hepatic impairment study, the mean total Cmax of aripiprazole was significantly lower in subjects with severe hepatic impairment compared with those with normal hepatic function (p = 0.04). The fraction of aripiprazole unbound (fu) was significantly greater for subjects with mild (p = 0.02) or severe hepatic impairment (p < 0.01) but not for those with moderate hepatic impairment (p = 0.09) compared with healthy controls. There were no meaningful differences in either the Cmax of unbound aripiprazole or CL/Fu between groups. The mean CL(R) of aripiprazole was negligible (0.04 mL/h/kg in controls and 0.19 mL/h/kg in patients with severe hepatic impairment). In the renal impairment study, the mean total Cmax values were numerically higher (approximately 40%) and the area under the plasma aripiprazole concentration-time curve from time zero to infinity was lower (approximately 19%) in renally impaired subjects versus those with normal renal function; the fu was comparable between groups. Aripiprazole CL(R) was approximately 3-fold higher in renally impaired subjects, but this difference was not statistically significant. No deaths or serious adverse events were reported during either study. CONCLUSION: A single aripiprazole 15-mg dose was well tolerated. There were no meaningful differences in aripiprazole pharmacokinetics between groups of subjects with normal hepatic or renal function and those with either hepatic or renal impairment. Adjustment of the aripiprazole dose does not appear to be required in populations with hepatic or renal impairment.     

Verapamil buffering effect on the abrupt elevation in blood pressure, linkage with microcirculatory blood flow

1 We studied the effects of verapamil on sudden elevation in blood pressure, microcirculation and arterial baroreflex sensitivity (BRS). 2 Thirty experiments (10 controls and 20 with verapamil) were performed in rabbits sedated using pentobarbital infusion (5 mg kg(-1) h(-1)). 3 BRS, mean femoral artery blood pressure (MAP), heart rate (HR) and ear lobe skin microcirculatory blood flow, estimated using microphotoelectric plethysmography (MPPG), were simultaneously measured during 30 min of verapamil infusion (20 mug kg(-1) min(-1)). BRS was assessed from HR and MAP responses to intravenous phenylephrine (Ph) and by power spectral analysis using transfer function (TF) from MAP to the HR (BRS(Ph,TF)). 4 Verapamil significantly increased microcirculatory blood flow, and decreased BRS(Ph,TF) and phenylephrine-induced abrupt elevation in MAP (MAP(AE)). 5 A significant inverse correlation was found between verapamil-induced changes in MAP(AE), BRS and in microcirculatory blood flow, measured before phenylephrine blood pressure ramps (DeltaMAP(AE) with DeltaBRS(TF), r = -0.47, P < 0.036; DeltaMAP(AE) with DeltaMPPG, r = -0.49, P < 0.025). 6 These results suggest involvement of the arterial baroreflex and vascular blood pressure-buffering mechanisms, their enhancement by verapamil, and thus a potential benefit of verapamil in cardiovascular conditions where patients present with abrupt high elevations in blood pressure.     

Circadian changes in estimated hepatic blood flow in healthy subjects.

Intravenous injections of indocyanine green (ICG) were given to 10 healthy supine subjects at 02.00, 08.00, 14.00 and 20.00 h. ICG plasma half-life, plasma clearance and estimated hepatic blood flow (EHBF), but not volume of distribution, varied significantly with time of day with EHBF being greatest at 08.00 h. This circadian rhythm in EHBF should be considered when evaluating the kinetics of high-clearance drugs at different times of day.     

Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure.

1. The pharmacokinetics, biliary excretion and binding of dibromosulphophthalein (DBSP) to plasma proteins and hepatic cytosol proteins have been studied in male rats with glycerol-induced acute renal failure (ARF). 2. The rate constants for hepatic uptake, efflux from liver to plasma and excretion into bile were all significantly decreased in rats with ARF. Furthermore, the plasma clearance of DBSP was also reduced. 3. The initial (0-10 min) and maximum biliary excretion rates of DBSP were both diminished in animals with ARF. The maximum excretion rate occurred between 5-10 min in control rats and 10-15 min in rats with ARF. However, there was no statistically significant change in the percentage dose recovered from bile after 30 min. 4. The plasma-protein binding of DBSP was decreased in rats with ARF and this change was due to a significant reduction in the association constant for the primary binding sites. 5. The binding of DBSP to ligandin (Y protein) was reduced by about 38% in rats with ARF but no change was noted in binding to Z protein. Reduced binding to ligandin was accompanied by decreased total liver glutathione S-transferase (GST) activity and a 36% reduction in the GST activity of ligandin. 6. The results support the contention that altered hepatic handling of cholephilic dyes in rats with ARF may be due to reduced binding to ligandin.