Efficacy and renal effects of enalapril therapy for hypertensive patients with chronic renal insufficiency.

The antihypertensive efficacy and renal effects of enalapril maleate therapy were evaluated in 13 hypertensive patients with chronic renal failure. Enalapril was administered as follows: alone; added to furosemide, clonidine hydrochloride, or atenolol; or in combination with any of the aforementioned drugs. Three patients did not complete the study; uncontrolled hypertension was the cause in two of these patients. In the remaining ten patients, short-term (mean +/- SD, 63 +/- 9 days) enalapril maleate therapy decreased the patient's seated blood pressure from 161/98 +/- 19/8 to 130/80 +/- 13/7 mm Hg. Furosemide was administered to eight patients; the dose of concomitant sympatholytic therapy was decreased in five of five patients. Serum potassium concentration increased from 4.1 +/- 0.3 to 4.5 +/- 0.3 mmol/L. Levels of urinary total protein excretion decreased from 2.23 +/- 2.05 to 1.08 +/- 1.45 g/d. Renal function (creatinine clearance, 0.58 +/- 0.21 mL/s) did not change from baseline. During long-term therapy, the rate of progression of renal insufficiency seemed to slacken in three of four patients with diabetic nephropathy. Thus enalapril can reduce blood pressure and proteinuria in hypertensive patients with chronic renal insufficiency. The possibility that enalapril can slow the progression of diabetic nephropathy remains to be confirmed by future studies.

Effect of bilateral nephrectomy on active renin, angiotensinogen, and renin glycoforms in plasma and myocardium.

In an attempt to clarify the relationship of the circulating and myocardial renin-angiotensin systems, active renin concentration, its constituent major glycoforms (active renin glycoforms I through V), and angiotensinogen were measured in plasma and left ventricular homogenates from sodium-depleted rats under control conditions or 2 minutes, 3 hours, 6 hours, and 48 hours after bilateral nephrectomy (BNX). Control myocardial renin concentration was 1.4+/-0.1 ng angiotensin I (Ang I) per gram myocardium per hour and plasma renin concentration was 6.7+/-1.1 ng Ang I per milliliter plasma per hour. Control myocardial angiotensinogen was 0.042+/-0.004 micromol/kg myocardium and plasma angiotensinogen was 1.5 micromol/L plasma. Two minutes after BNX and corresponding stimulation of renin secretion by anesthesia and surgery, plasma renin concentration was increased disproportionately compared with myocardial renin. Three, 6, and 48 hours after BNX, renin decay occurred significantly faster from the plasma than from the myocardium. Forty-eight hours after BNX, myocardial renin concentrations had fallen to 15% of control values, while myocardial angiotensinogen concentrations had increased 12-fold and plasma angiotensinogen concentrations had increased by only 3.5-fold. Myocardial renin glycoform proportions were identical in myocardial homogenates and plasma in control animals. At 6 hours BNX, the proportions of plasma active renin glycoforms I+II fell, while those in the myocardium significantly increased. We conclude that in control rats, active renin and active renin glycoforms are distributed as if in diffusion equilibrium between plasma and the myocardial interstitial space. After BNX, myocardial renin concentration falls dramatically, suggesting that most cardiac renin is derived from plasma renin of renal origin. After BNX, renin glycoforms I+II are preferentially cleared from the plasma but preferentially retained by the myocardium. Control myocardial angiotensinogen concentrations are too low to result from simple diffusion equilibrium between plasma and the myocardial interstitium.

Renal secretion and hepatic clearance of human multiple renin forms.

Human active renin can be separated into at least five forms by isoelectric focusing. The present study assessed the preferential renal secretion and hepatic degradation of renin forms in humans. The renin form profile of secreted renal renin was determined before transplant in an ex vivo kidney donor perfusion system and compared with the peripheral plasma multiple renin form profile of normal subjects. The effect of hepatic degradation on renin forms was assessed in hepatic vein plasma in comparison with infrarenal vena cava plasma in hypertensive patients during renal vein renin studies. The results revealed a significantly greater proportion of the more basic forms in the perfusate of donor kidneys compared with normal plasma. In hypertensive patients the proportion of the more basic renin forms in the hepatic vein was significantly decreased in comparison with the infrarenal vena cava. Thus, the human kidney may preferentially secrete the more basic renin forms. In contrast, the liver preferentially degrades the more basic forms, giving these forms a shorter plasma half-life. The preferential secretion and clearance of the more basic forms of renin may contribute to short-term control of human renin-angiotensin system activity.

Validity of creatinine clearance estimates in the assessment of renal function.

In clinical practice, estimations of renal function are commonly used to calculate the appropriate dose for drugs that are renally cleared. Continuous-infusion inulin clearance (CLIN), 4-hour creatinine clearance (CLCR,m), and 24-hour creatinine clearance (CLCR,a) were measured in 109 subjects (86 men and 23 women) with varying degrees of stable renal function (CLIN, 6 to 209 ml/min) and compared with CLCR values as predicted by five equations on the basis of plasma creatinine concentrations, age, weight, and/or height. The CLCR,m was positively correlated with CLIN (r = 0.92; p less than 0.0001) but exceeded CLIN by 15% between the range of 30 and 209 ml/min (CLIN). Similarly, CLCR,a correlated well with both CLCR,m (r = 0.84; p less than 0.0005) and CLIN (r = 0.84; p less than 0.0001). The relative role of tubular secretion in the overall clearance of creatinine increased with declining CLIN and exceeded 40% when CLIN was below 30 ml/min. CLCR estimated by the Cockcroft-Gault and Mawer methods did not significantly differ from either CLCR,m or CLCR,m, whereas the other equations generally underestimated CLCR. Among the numerous mathematical equations, CLCR as estimated by the method proposed either by Mawer or Cockcroft and Gault was the best predictor of CLIN (CLIN = 1.05CLRCR - 18.38 or CLIN = 1.12CLCR - 20.60, respectively; r = 0.81; p less than 0.0001). The present data support the use of estimator equations proposed by Cockcroft and Gault or Mawer for rapid estimation of renal function in the clinical setting.

Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease.

The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide, morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were determined by sensitive and specific RIA procedures. Pharmacodynamics were assessed by pupillometry and vital sign determinations. Codeine elimination half-life and mean residence time were increased significantly in the hemodialysis group (18.69 +/- 9.03 hours and 12.77 +/- 7.09 hours, mean +/- SD, respectively) compared with the healthy volunteer group (4.04 +/- 0.60 hours and 3.90 +/- 0.52 hours, respectively). The total body clearance and volume of distribution of codeine were not significantly different between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites were also not significantly different between the groups, in part as a result of significant interpatient variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen may be required in some patients with uremia receiving multiple-dose codeine therapy.

The disposition and dynamics of labetalol in patients on dialysis.

The disposition of labetalol was assessed in 16 patients on dialysis after intravenous dosing with 0.7 to 1.0 mg/kg during an interdialytic period and just before hemodialysis (n = 8) and during continuous ambulatory peritoneal dialysis (CAPD) (n = 8). The plasma concentration time data exhibited triexponential decay in all patients. The terminal t 1/2 of labetalol was 12.90 +/- 4.68 hours, the total body clearance was 1198.2 +/- 249.4 ml/min, and the AUC was 921.4 +/- 175.2 ng hr/ml during the interdialytic period. No significant changes were observed in these parameters after dosing with labetalol just before dialysis. The hemodialysis clearance of labetalol was 30.67 +/- 5.49 ml/min, and only 0.189 +/- 0.042 mg of labetalol was removed by hemodialysis. The terminal t 1/2 averaged 13.05 +/- 6.32 hours during CAPD. Steady-state volume of distribution, total body clearance (Clp), and CAPD clearance were 10.39 +/- 2.77 L/kg, 1397.2 +/- 372.3 ml/min, and 1.94 +/- 0.65 ml/min, respectively. The fraction of the dose recovered in the CAPD dialysate during the 72-hour study period was 0.14% +/- 0.09%. The decay of the antihypertensive effect of labetalol was gradual and paralleled the decline in the log plasma concentration. There was a significant correlation between labetalol plasma concentration and the fall in supine diastolic and mean blood pressure after the interdialytic dose and during CAPD. Although labetalol is removed by dialysis, dialysis does not significantly enhance Clp.

Epoetin enhances erythropoiesis in normal men undergoing repeated phlebotomies.

Epoetin may enhance autologous blood donation, but efficacy and dose response have not been established. This multicenter, double-blind trial compared intravenous placebo (n = 23) with epoetin beta, 250 U/kg (n = 23), 500 U/kg (n = 19), and 1000 U/kg (n = 22), administered three times weekly for 26 days. Normal men (age, 28 +/- 7 years; mean +/- SD) received phlebotomies up to three times weekly as long as the hemoglobin remained greater than or equal to 12 gm/dl. Subjects treated with epoetin donated 32% more units of blood (p less than 0.05) compared with placebo. A dose response was not observed. Platelet counts increased with epoetin compared with placebo, but platelet function and bleeding time did not change. Prothrombin times increased and partial thromboplastin times decreased with both epoetin and placebo. The supernatant of packed red blood cells collected after multiple phlebotomies and stored 42 days had slightly lower glucose concentrations and pH after therapy with epoetin. Blood pressure did not change with epoetin or placebo. These findings support the efficacy and safety of epoetin for enhancing the erythropoietic response of normal subjects during intensive phlebotomy.

Angiotensin-converting enzyme inhibitors in chronic renal failure.

In contrast to some other antihypertensive drugs, angiotensin-converting enzyme (ACE) inhibitors lower glomerular capillary pressure, decrease proteinuria, and may halt progressive glomerular injury and loss of renal function in experimental chronic renal failure (CRF). Although these favourable effects of ACE inhibition may result from alterations in glomerular haemodynamics, there is some evidence to show that ACE inhibitors may reduce glomerular injury through other mechanisms. CRF in man may result from a variety of insults to the kidney. However, it is not known whether, or under which conditions, glomerular capillary pressure is elevated in this heterogeneous population. Limited data suggest that renal haemodynamics (and perhaps glomerular capillary pressure) may depend in part on the level of systemic blood pressure. In addition, several studies have demonstrated a positive correlation between systemic blood pressure and the rate of progression of CRF. ACE inhibitor therapy generally lowers systemic blood pressure, does not alter renal function and decreases proteinuria in patients with CRF. The reduction in proteinuria appears to be variable and may depend on pretreatment glomerular haemodynamics and/or the activity of the renin-angiotensin-aldosterone system. Preliminary evidence also suggests that ACE inhibitors may slow the progression of renal disease in humans with CRF. However, this effect, like the reduction in proteinuria, has not been observed consistently in all patients. In addition, it is not clear whether these effects on proteinuria and progression of disease are unique to ACE inhibitor therapy, since the lowering of systemic blood pressure with other drugs may have similar effects. The heterogeneity of the response to ACE inhibition suggests that there may be interpatient differences in glomerular haemodynamics in CRF, perhaps related to systemic blood pressure or the underlying disease process. Studies to date indicate that ACE inhibitors exert their beneficial effect by lowering glomerular capillary pressure and that not all patients will benefit from therapy with regard to proteinuria or amelioration of disease progression. However, further investigation of the haemodynamic and non-haemodynamic effects of ACE inhibitors, as well as the variability of response, may ultimately allow the selection of those patients who would benefit from such therapy.

Antihypertensive and humoral effects of nifedipine in essential hypertension uncontrolled by hydrochlorothiazide alone.

This double-blind placebo controlled study investigated the antihypertensive and humoral effects of nifedipine capsules in patients with essential hypertension inadequately controlled (seated diastolic blood pressure greater than or equal to 95 mm Hg) by hydrochlorothiazide (HCTZ) alone. Nifedipine acutely (first dose) lowered supine blood pressure but did not change supine plasma renin activity (PRA) or aldosterone concentration. In contrast to placebo, short-term treatment (10 weeks) with nifedipine (n = 9, mean dose 43 +/- 16 mg daily) added to HCTZ (50 mg daily) significantly decreased seated blood pressure by 8.6 +/- 10.8/11.5 +/- 6.9 mm Hg. Neither nifedipine or placebo therapy altered PRA, plasma aldosterone concentration or 24 hour urinary aldosterone excretion. Nifedipine frequently caused mild vasodilator symptoms but these did not limit therapy in most patients. There was no correlation between PRA, plasma aldosterone concentration or 24 hour urinary aldosterone excretion and the acute or short-term blood pressure response to nifedipine in these diuretic treated patients. The acute blood pressure response to nifedipine did not predict short-term efficacy. Thus, nifedipine added to a diuretic is generally well-tolerated, effectively lowers blood pressure, and does not stimulate the renin-angiotensin-aldosterone (RAA) axis. Additionally, in diuretic treated patients, the activity of the RAA axis and initial blood pressure response to nifedipine are not predictive of short-term efficacy.

Acute stimulation of renin secretion changes the multiple form profile of active plasma renin.

Active renin is composed of multiple forms with variable isoelectric points. In this study, the relative proportions of five major active renin forms in human peripheral venous plasma were compared before and 2 h after stimulation of renin secretion with both converting enzyme inhibition (quinapril) and upright posture in five patients with essential hypertension. The five major active renin forms were separated by shallow gradient isoelectric focusing and quantitated by radioimmunoassay of generated angiotensin I. Plasma renin activity increased from 1.2 to 5.1 ng AI/mL/h (P less than .05). This was accompanied by a significant increase in the proportions of the two most basic renin forms and a significant decrease in the proportion of the most acidic form in venous plasma. Although the mechanism cannot be determined from this study, the altered renin form profile observed could have resulted from preferential renal secretion and/or altered hepatic extraction of the more basic forms. An altered renin form profile in response to acute stimulation has important physiologic implications. Since the relatively basic renin forms are preferentially degraded they possess shorter half-lives. Additionally, the multiple forms of active renin may be functionally heterogenous. Thus, acute stimulation of renin secretion may result in circulating renin with a shorter duration of action and different functional effects than renin released under steady state conditions.

Effect of acute and chronic losartan therapy on active and inactive renin and active renin glycoforms.

Plasma active renin consists of multiple glycoforms, which are differentially stored and secreted by the kidney, have varying plasma half-lives, and appear to have differing effects on renal sodium and water metabolism. Acute stimulation of renal renin secretion results in a disproportionate increase in plasma concentrations of the less negatively charged renin glycoforms and a decrease in the plasma half-life of active renin. The effects of chronic stimulation have not been well studied. We studied the effect of acute and chronic (42 days) stimulation of the renin angiotensin system with the AT1 selective angiotensin II receptor antagonist losartan on plasma active renin, active renin glycoforms separated by isoelectric focusing, and inactive renin in 11 essential hypertensive patients. A single 50 mg dose of losartan significantly increased plasma active renin concentration (ARC) from a pretreatment baseline of 3.2 +/- 1.1 to 7.2 +/- 2.3 ng AI/mL/h, 4 h postdose. This was primarily due to an increase in plasma concentrations of the less negatively charged active renin forms. After 42 days of losartan monotherapy, plasma ARC at losartan trough had increased significantly to 7.8 +/- 3.1 ng AI/mL/h, although the proportions of active renin forms were identical to baseline. Plasma ARC also increased significantly from 7.8 +/- 3.1 to 14.9 +/- 6.0 ng AI/mL/h acutely after the losartan dose on day 42 primarily due to increased plasma concentrations of less negatively charged active renin forms. Although plasma inactive renin concentrations did not change acutely after losartan dosing on day 1 or 42 they did increase from 27.3 +/- 7.8 before losartan day 1 to 37.0 +/- 13.7 ng AI/mL/h (P = .14) before losartan day 42. Thus, both acute and acute on chronic stimulation of renal renin secretion increased circulating ARC and shifted the profile of circulating renin toward the less negatively charged forms but did not change inactive renin concentrations. Chronic stimulation of renal renin secretion with losartan increased plasma concentrations of both active and inactive renin, but did not alter the proportions of active renin forms. Since the less negatively charged active renin forms have relatively short plasma half-lives, acute, but not chronic renal renin secretion is associated with a change in plasma renin half-life. Chronic stimulation of renal renin secretion with losartan presumably increased renin gene expression and resulted in increased constitutive secretion of inactive renin, increased constitutive secretion of negatively charged active renin forms, and increased renal storage of less negatively charged renin forms that were then available for acute regulated release.

Correlation of office and ambulatory blood pressure measurements with urinary albumin and N-acetyl-beta-D-glucosaminidase excretions in essential hypertension.

Ambulatory blood pressure (ABP) correlates better than office blood pressure with hypertensive changes in the heart and vasculature. Using the 24-hour urinary excretions of albumin and N-acetyl-beta-D-glucosaminidase (NAG) as markers, we examined the relationship between office and ABP and target-organ changes in the kidney in 42 untreated patients with essential hypertension. Mean urinary albumin excretion was 23.2 +/- 34.3 mg/day and mean urinary NAG excretion was 45.1 +/- 22.9 nmol/hr/mg creatinine. Urinary albumin excretion was positively correlated with both office and mean 24-hour systolic blood pressure (r = 0.31, P less than 0.05; and r = 0.44, P less than 0.01, respectively). Urinary NAG excretion was positively correlated with 24-hour ambulatory systolic, diastolic, and mean blood pressure (r = 0.32, P less than 0.05; r = 0.32, P less than 0.05; and r = 0.39, P less than 0.05, respectively), but not with office blood pressure. Thus, urinary albumin and NAG excretions are positively correlated with blood pressure and may be useful markers of renal involvement in patients with essential hypertension. Additionally, ABP may be more reliable than office blood pressure in identifying those patients at risk for hypertensive target-organ changes in the kidney.

Urinary albumin and N-acetyl-beta-D-glucosaminidase excretions in mild hypertension.

Renal effects of mild hypertension and therapy have not been established. Since urinary albumin and N-acetyl-beta-D-glucosaminidase excretions reflect renal effects of hypertension, they were related to blood pressure, other cardiovascular risk factors, cardiac target organ effects, and response to therapy in mild hypertension (diastolic blood pressure 85-99 mm Hg). Participants were from two clinics of the Treatment of Mild Hypertension Study (TOMHS), a multicenter randomized, double-blind, controlled trial. Participants received nutritional-hygienic therapy and one of five active drugs or placebo. Urinary albumin and N-acetyl-beta-D-glucosaminidase excretions were assessed prospectively using office "spot" collections from one clinic (n = 213) and retrospectively using overnight collections from the other clinic (n = 210). Relationships were determined between protein excretions and blood pressure, age, gender, race, blood glucose, cholesterol concentrations, and indices of body mass and left ventricular mass and function at baseline. Treatment effects were assessed after 3 to 12 months. Spot and overnight albumin excretions related positively to baseline systolic blood pressure by univariate analyses. Spot albumin excretion related positively to systolic blood pressure, age, creatinine clearance, and left ventricular function while overnight albumin excretion related positively to left ventricular mass and female gender by multiple regression analyses. Spot, but not overnight, albumin excretion declined significantly with active drug therapy. N-acetyl-beta-D-glucosaminidase excretion did not relate to blood pressure or decline with therapy. The combined results suggest albumin excretion correlates with blood pressure, decreases with antihypertensive drug therapy, and is associated with greater left ventricular function and mass, as well as glomerular filtration rate, even at mild levels of hypertension.

Effects of hemodialysis on plasma protein binding of bepridil.

The effects of end-stage renal disease (ESRD) and hemodialysis on the in vitro plasma protein binding of bepridil hydrochloride were investigated. The possible influence of bepridil metabolites on bepridil-protein binding in ESRD patients was also examined. Plasma samples were obtained from six patients with ESRD. Bepridil-plasma protein binding was measured by microequilibrium dialysis after addition of freshly prepared bepridil-14C (239 microCi/mg) at a final concentration of 2 micrograms/mL. The percentage of free bepridil in peripheral venous samples drawn on a nondialysis day was lower (i.e., binding was greater) in the patients with ESRD relative to previous observations in healthy subjects (0.15% +/- 0.04% versus 0.31% +/- 0.05% (mean +/- SD). The plasma concentrations of alpha-1-acid glycoprotein (AAG), the principal bepridil binding protein, were also higher in ESRD patients (110 +/- 32 mg/dL) than previously reported in healthy subjects. Although hemodialysis resulted in significant increases in AAG, total protein, and albumin concentrations, no significant difference in bepridil-plasma protein binding was detected between predialysis and postdialysis peripheral venous samples in the presence (0.16 versus 0.18) or absence (0.20 versus 0.17) of bepridil metabolites. The percentage of free bepridil in plasma from both the arterial and venous limbs of the dialyzer during hemodialysis (means of free bepridil ranged from 0.24-0.28%) was higher than in samples drawn from a peripheral vein. This displacement of bepridil from its binding sites as blood passes through the dialyzer may have been owing to the presence of high local concentrations of plasticizers. Confirmation of this hypothesis will require further investigation.

Disposition of guanadrel in subjects with normal and impaired renal function.

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

Pharmacokinetics of loratadine in patients with renal insufficiency.

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearance less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2 beta were observed between the three groups (8.7 +/- 5.9, 7.6 +/- 6.9, 8.6 +/- 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC infinity 0 however was significantly greater in group II subjects: (212.4 +/- 37.8, 469.5 +/- 95.4, 325.2 +/- 114.6 ng.hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half-life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.

Pharmacokinetics of codeine after single- and multiple-oral-dose administration to normal volunteers.

The pharmacokinetics of codeine, codeine glucuronide, morphine, and morphine glucuronide were assessed after single- (60 mg) and multiple-dose (60 mg every six hours for nine doses) oral administration of codeine sulfate to six normal volunteers. Multiple blood and urine samples were collected after administration of the single- and last multiple-oral doses. Drug concentrations were analyzed using radioimmunoassay techniques. No significant alterations in codeine pharmacokinetics were noted after multiple-dose oral administration. However, accumulation of morphine during multiple dosing was significant (AUC24 = 102 +/- 33 ng/mL/hr after single dose versus 212 +/- 118 ng/mL/hr after the last multiple dose). Peak concentration and AUC24 data for morphine glucuronide indicated that significant accumulation of this compound occurs upon multiple-dose administration. These data indicate that morphine and morphine glucuronide serum concentrations are significantly increased during chronic oral codeine therapy and suggest that morphine, and perhaps morphine glucuronide, contribute significantly to the analgesic activity of chronic oral codeine therapy.

Disposition of famotidine in renal insufficiency.

The disposition of famotidine was evaluated in 18 patients; Group 1, mild renal insufficiency, [creatinine clearance (CLCR): 30-60 mL/min]; Group 2, moderate to severe renal insufficiency (CLCR: 10-30 mL/min); Group 3, end-stage renal disease requiring maintenance hemodialysis (anuric). Blood and urine samples were obtained over a 72-hour period. Plasma concentration-time data demonstrated biexponential decay. The terminal elimination half-life was prolonged in Group 3 (18.6 +/- 5.7 hr) compared with Groups 1 (9.3 +/- 2.3 hr) and 2 (9.7 +/- 1.7 hr), P less than .05. Steady-state volume of distribution ranged from 0.80 to 1.26 L/kg but did not differ among the groups. Total body clearance (CLp) and renal clearance were significantly lower in Groups 2 and 3 patients compared with Group 1 patients. Nonrenal clearance was not related to CLCR. The CLp correlated well with CLCR (CLp = 1.59 CLCR + 33.8, r = 0.830, P less than .05). These data indicate that dosage adjustment may be necessary in patients who have renal insufficiency.

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, in patients with various degrees of renal function.

Single- and multiple-dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, were determined after oral administration of 20 mg quinapril HCl on day 1 and days 4 through 10 in 17 normotensive subjects with various degrees of renal function. Blood and urine samples were collected over 72- and 24-hour periods, respectively, after the first single dose and last multiple dose for measurement of quinapril and quinaprilat concentrations. The renal clearance of quinapril and quinaprilat decreased with increasing renal insufficiency but did not result in significant changes in quinapril pharmacokinetics in patients with renal impairment. In contrast, quinaprilat maximum plasma concentration, trough and peak steady-state plasma concentrations, area under the plasma concentration-time curve, and half-life increased significantly with increasing renal insufficiency. The disposition of quinapril and quinaprilat was unchanged from single to multiple doses. Small changes in the pharmacokinetic disposition of quinapril, together with a decreased rate of quinaprilat elimination, resulted in increased quinaprilat plasma concentrations following administration of both single and multiple quinapril doses to normotensive patients with renal impairment. Thus, quinapril dosage adjustment may be required in some patients with renal impairment.

Disposition of minoxidil in patients with various degrees of renal function.

The disposition of minoxidil was evaluated after a 5 mg oral dose in 24 subjects with various degrees of renal function. Patients were divided into four groups based on a 24-hour ambulatory creatinine clearance (Clcr): Group I (n = 6) Clcr greater than 90 mL/min, Group II (n = 6) Clcr 50-80 mL/min, Group III (n = 5) Clcr of 30-49 mL/min, and Group IV (n = 7) Clcr less than 30 mL/min. Blood and urine samples obtained over 36 hours were analyzed for minoxidil by a high pressure liquid chromatography technique. Maximum plasma concentration (Cmax) and time to reach Cmax did not differ among the four groups. The terminal elimination half-life was prolonged in Group IV subjects (8.87 +/- 6.12 hours) (mean +/- SD) compared to those in Groups I, II and III (1.38 +/- 0.16, 1.99 +/- 0.45 and 2.42 +/- 0.53 hours, respectively). Apparent total body clearance (Clp/F) decreased as renal function declined; Clp/F = 0.82(Clcr) + 21.8, r = 0.739, P = 0.0001. Renal clearance and apparent nonrenal clearance also were significantly correlated with Clcr. The apparent volume of distribution significantly increased as renal function declined. Thus, the disposition of minoxidil is significantly delayed and dosage adjustment may be necessary in patients with renal insufficiency.