Double-blind comparison of captopril and enalapril in mild to moderate hypertension.

To compare the antihypertensive and humoral effects of the angiotensin-converting enzyme inhibitors captopril and enalapril, 20 patients with essential hypertension, not receiving treatment for 2 weeks and consuming a prescribed sodium ion intake, were randomly assigned to two parallel, double-blind treatment groups with stratification based on race and untreated seated diastolic blood pressure. These groups received a placebo (day -1) followed by either captopril, 200 mg every 12 hours (n = 9), or enalapril maleate, 20 mg every 12 hours (n = 11), alone (days 1 to 14) and then with hydrochlorothiazide, 25 mg every 12 hours (days 16 to 28). Captopril and enalapril were coadministered alone (day 15) and with hydrochlorothiazide (day 29) to assess whether further decreases in blood pressure would occur. Captopril and enalapril alone caused comparable decreases (p less than 0.05) in the mean 12 hour time-averaged seated diastolic blood pressure from values on day -1 (placebo), on day 1 (11 and 9 mm Hg, respectively) and day 14 (8 and 7 mm Hg, respectively). The addition of hydrochlorothiazide further decreased (p less than 0.05) blood pressure in each group (7 and 8 mm Hg, respectively) from values on day 14. Combined use of captopril and enalapril did not result in further reduction. Coupled with the comparable changes observed in each treatment group in serum angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration, these data support the view that captopril and enalapril have similar antihypertensive effects and mechanisms.

Urinary excretion of D-glucaric acid by severely burned patients.

The 24-hr excretion of urinary D-glucaric acid (UGA) has been measured in 5 seriously burned adults and compared with 6 healthy adults. In the burn patients mean UGA was 14.4 +/- 5.4 (+/- SD) mumoles/day and 28.7 +/- 6.5 mumoles/day in controls (p less than 0.002). In a 6-year-old female, UGA was also found to be very low. In a seventh burn patient, an adult male taking 20 mg of fluphenazine until his injury, his UGA was still in the normal range (29 mumoles/day) on the day of admission but descended to 21 mumoles/day at 2 days, to 16 at 4 days, and to 13 at 6 days. Treatment with fluphenazine was then reinstituted and on the tenth day UGA was 28 mumoles/day, indicating that after thermal injury UGA can respond to drugs. Although the inference has not been proved that decreased UGA corresponds to a decreased activity of drug metabolism, there is evidence of a strong correlation between increased UGA and increased drug metabolism. A decrease of UGA in disorders that generally lower metabolic activity supports a possible correlation in severe burns. If drug metabolism activity is lowered in the seriously burned patient, drug overdose may well result from the usual clinical doses.

Pharmacokinetics of the aldose reductase inhibitor tolrestat: studies in healthy young and elderly male and female subjects and in subjects with diabetes.

Tolrestat is an aldose reductase inhibitor undergoing clinical trials in diabetic subjects that may reduce the severity of chronic tissue damage associated with hyperglycemia. These studies were conducted to evaluate the pharmacokinetics of tolrestat in healthy young and elderly male and female subjects and in young and elderly subjects with diabetes. The drug was administered in a multiple-dose regimen, and steady-state parameters were obtained. There were no important gender-related differences, but mean values for apparent oral clearance, renal clearance, and corresponding unbound parameters were significantly lower for the elderly healthy subjects than for the young healthy subjects. The drug is highly bound to plasma proteins, and the unbound fraction (0.75%) did not differ among the subjects. The results from young and elderly diabetic subjects suggest that diabetes per se has no influence on tolrestat disposition but that there is an age-related reduction in apparent oral clearance (30 versus 18 ml/hr/kg) and a corresponding increase in the minimum steady-state plasma concentration (1.2 versus 1.9 micrograms/ml). These data indicate a possible need to reduce the dose of tolrestat in elderly subjects, assuming the same concentration-response relationship.

Bromfenac disposition in patients with impaired kidney function.

OBJECTIVES: To compare the pharmacokinetics of bromfenac among normal subjects and renally compromised patients and patients with end-stage renal disease. METHODS: Bromfenac pharmacokinetics were examined after a single 50 mg oral dose in 18 subjects with normal kidney function, 12 subjects with decreased kidney function, and 10 dialysis-dependent subjects. Protein binding was assessed by equilibrium dialysis. RESULTS: Mean peak concentrations and areas under the concentration versus time curve ranged from 3.3 to 3.9 micrograms/ml and 5.1 to 6.9 micrograms.hr/ml, respectively. The mean unbound fraction in the subjects receiving dialysis (0.29%) was nearly twice that in the subjects with normal kidney function (0.17%) and in the subjects with impaired kidney function (0.16%), but no differences were detected in clearance, volume of distribution, or their free fraction-corrected counterparts. Bromfenac half-life nearly doubled in the impaired and dialysis groups but was shorter than the anticipated 8-hour dose interval. Eight subjects had a total of 11 study events; none were serious and all were self-limited. CONCLUSIONS: These findings suggest that no dosage adjustment is necessary in patients with impaired kidney function, but clinical monitoring appropriate for their individual condition is recommended.

Population distribution and effects on drug metabolism of a genetic variant in the 5' promoter region of CYP3A4.

BACKGROUND: There are large interindividual differences in CYP3A4 expression and in the metabolism of drug substrates for this enzyme. We and others have identified a polymorphism in the 5' promotor region of the CYP3A4 gene; however, its functional significance is not currently known. This study was conducted to determine whether this polymorphism plays a clinically important role in determining CYP3A4 phenotype. METHODS: An adenine (A) to guanine (G) transition was identified in the 5' promotor region of the CYP3A4 gene at position -292 (from the start codon), in a sequence motif known as the nifedipine-specific element. The frequency of this polymorphism was assessed in 802 healthy volunteers from five broadly defined racial groups. The population distribution of the G allele in these groups was as follows: white Americans (3.6%; n = 273), black Americans (54.6%, n = 186), Hispanic Americans (9.3%; n = 188), Japanese Americans (0.0%; n = 77), and Chinese Americans (0.0%; n = 78). In a subsequent study, 90 additional black Americans were genotyped, and a subset of the homozygous subjects (AA, n = 8; GG, n = 23) were given the CYP3A4 probe substrates erythromycin and nifedipine to allow genotype-phenotype comparisons to be made. RESULTS: There was no difference in the rate of CYP3A4-dependent demethylation of erythromycin (erythromycin breath test) or the pharmacokinetics of nifedipine or its CYP3A4-dependent metabolite dehydronifedipine between the two genotype groups (AA or GG). CONCLUSIONS: This promotor region polymorphism does not appear to play a major role in determining constitutive CYP3A4 expression.

Absolute and comparative subcutaneous bioavailability of ardeparin sodium, a low molecular weight heparin.

Ardeparin sodium (Normiflo, Wyeth-Ayerst) is a low molecular weight heparin undergoing clinical evaluation as an antithrombotic agent. The objective of this study was to evaluate the absolute and comparative bioavailability of ardeparin following subcutaneous administration of three different formulations [two formulations of ardeparin at 10,000 anti-factor Xa (aXa) U/ml, but with different preservatives, and a 20,000 aXa U/ml formulation]. The study was conducted using a randomized 4-period crossover design (three subcutaneous treatments and one intravenous treatment) in 24 healthy subjects, and the pharmacokinetics of ardeparin were characterized by plasma anti-factor IIa (aIIa) and anti-factor Xa (aXa) activities. The mean absolute bioavailability of ardeparin based on aIIa activity ranged from 62% to 64% and the mean absolute bioavailability based on aXa activity ranged from 88% to 97%. Based on bioequivalence testing criteria, the three ardeparin formulations were bioequivalent.

Comparative evaluation of the effects of labetalol, verapamil and diltiazem on antipyrine and indocyanine green clearances.

The effects of labetalol, diltiazem and verapamil on antipyrine and indocyanine green clearance were evaluated in a placebo-controlled, repeated measures evaluation. Twelve healthy subjects received either labetalol (200 mg every 12 hours), diltiazem (90 mg. every 8 hours), verapamil (80 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the morning of Day 3 immediately following their dose, the subjects assumed the supine position for 90 minutes, after which time a 0.5 mg/kg dose of indocyanine green was administered. Blood samples were obtained serially over a 20 minutes period for indocyanine green plasma concentration determinations by HPLC. Ten minutes later, subjects ingested a 1.2 Gm. dose of antipyrine and blood samples were obtained over a 48 hour period for antipyrine plasma concentration determinations by HPLC. A 2 week washout period separated treatment sequences. Mean (SD) antipyrine clearance (L/hr/kg) following diltiazem [0.028 (0.010)] and verapamil [0.030 (0.012)] treatment was significantly lower than that observed following placebo [0.039 (0.012)]. Antipyrine clearance following labetalol administration [0.033 (0.010)] was not significantly different from that observed following placebo, diltiazem or verapamil administration. No effects of these drugs on indocyanine green clearance could be detected.

The pharmacokinetics of venlafaxine when given in a twice-daily regimen.

The comparative bioavailability of the novel antidepressant venlafaxine and its pharmacologically active metabolite O-desmethylvenlafaxine was assessed when venlafaxine was given orally twice daily (75 mg bid) or 3 times daily (50 mg tid). Eighteen healthy subjects participated in an open-label, randomized, two-period, crossover study lasting 12 days. Each subject was randomly assigned to take venlafaxine according to a bid or a tid regimen through day 8 and was crossed over to the other regimen on days 9 to 12. The daily dose was titrated up to 150 mg/d and was held constant on days 5 to 12. Plasma samples for quantitation of venlafaxine and O-desmethylvenlafaxine were obtained during a 24-hour steady-state interval on days 8 and 12. Analysis of variance showed no significant differences between the two venlafaxine regimens for peak concentration (Cmax), area under the curve during 24 hours (AUC0-24), trough concentration, or fluctuation ratio for venlafaxine or O-desmethylvenlafaxine in plasma. The bioequivalence ratios for Cmax and AUC0-24 of both compounds were calculated to compare the bid regimen and the tid regimen. The mean value for each of the 4 ratios was between 96 and 100%, and the 90% confidence limits around each ratio were within 90 to 110%. These results indicate that dividing a daily 150-mg venlafaxine dose into 2 or 3 doses provides equivalent total exposure and peak plasma concentrations of venlafaxine and O-desmethylvenlafaxine, its active metabolite. Therefore, based on pharmacokinetic considerations, it appears that the same daily dose of venlafaxine can be given in either two or three divided doses without compromising efficacy.

The dose proportionality of the pharmacokinetics of ardeparin, a low molecular weight heparin, in healthy volunteers.

Ardeparin is a low molecular weight heparin currently being evaluated as an antithrombotic agent. The objective of this investigation was to assess the effects of dose on the pharmacokinetics of ardeparin after subcutaneous administration. Eighteen healthy subjects received doses of 30 U/kg, 60 U/kg, and 100 U/kg antifactor Xa (aXa) of ardeparin by subcutaneous injection. Plasma antifactor IIa (aIIa) activity levels after the 30- and 60-U/kg doses of ardeparin were too low to reliably characterize the disposition of the drug. However, the pharmacokinetics of ardeparin could be characterized by using pharmacodynamic measurements of plasma aXa activity. The rate of absorption of ardeparin after subcutaneous administration did not change with increasing dose. The volume of distribution (Vd) of ardeparin was small, reflecting minimal distribution outside the intravascular space, and was independent of dose. The total clearance of ardeparin, however, decreased with increasing dose, and half-life (t1/2) was prolonged at the higher doses. Within the observed dose range, a doubling of the ardeparin dose resulted in an area under the plasma aXa activity-versus-time curve (AUC) that was approximately 25% greater than expected on the basis of linear disposition. The differences in AUC and clearance between the three doses suggest that the mechanism of elimination of ardeparin is saturable.

Lovastatin does not affect oral glucose tolerance in hypercholesterolemic patients.

In 15 non-diabetic Type II hypercholesterolemic patients, the effect of 80 mg lovastatin daily on oral glucose tolerance was investigated. Using a randomized, double-blind, two-panel, parallel design, patients on a low cholesterol diet received lovastatin (n = 7) or placebo (n = 8) for 6 weeks. After 6 weeks of treatment, patients receiving lovastatin had a significant reduction in total cholesterol (30%), LDL-cholesterol (36%), and triglycerides (26%). Time courses of plasma glucose and serum insulin changes from baseline after the oral glucose tolerance test were evaluated by AUC. No statistically significant differences were observed in the AUC of changes from baseline between treatment groups or within either treatment group at prestudy, 6 weeks, and poststudy. No patient had a clinically important laboratory or clinical drug-related adverse effect during the study. This study demonstrated that short-term administration of 80 mg lovastatin daily effectively lowers cholesterol without having adverse effects on oral glucose tolerance.

Lack of pharmacokinetic interaction between oral pantoprazole and cisapride in healthy adults.

Pantoprazole, an irreversible proton pump inhibitor, may be administered with cisapride, a prokinetic agent. As increased cisapride concentrations may result in longer electrocardiogram (ECG) QTc intervals, a crossover study was conducted in healthy subjects to evaluate the oral pharmacokinetic interaction between cisapride (20 mg) and pantoprazole (40 mg). After dosing, serial blood samples and 12-lead ECGs were collected, and cisapride plasma concentrations were quantitated. For cisapride alone, mean parameter values were the following: peak concentration (Cmax), 56 ng/mL; time to Cmax (tmax), 1.7 hours; area under the concentration-time curve (AUC), 426 ng x h/mL; and terminal half-life (t1/2), 5.8 hours. Pantoprazole coadministration did not alter cisapride AUC or other pharmacokinetic parameters except for a slight 17% decrease in Cmax' resulting in 90% confidence limits of 79% to 88%, which were marginally outside strict bioequivalence limits. In addition, cisapride did not affect ECG QTc intervals, with or without pantoprazole. Therefore, no dosage adjustment is needed when pantoprazole and cisapride are coadministered.

Pharmacokinetics of pentobarbital, quinidine, lidocaine, and theophylline in the thermally injured rat.

Previous studies have shown that rats with 15% third-degree burns show a severe depression in various in vitro hepatic drug-metabolizing enzymes. This effect was assessed in vivo by measuring the disposition of four liver-metabolized drugs in 16% third-degree burned rats at 7 d postburn. Compared with pair-fed control rats, pentobarbital demonstrated a significantly prolonged clearance and elimination half-life without a change in volume of distribution. Quinidine demonstrated a significantly increased volume of distribution and a significantly decreased clearance without a change in elimination half-life. Lidocaine showed a significantly increased volume of distribution. Theophylline, which is only 50% metabolized in the rat, showed no changes in any pharmacokinetic parameters. The free drug fractions of quinidine and lidocaine were found to be significantly decreased at 1 d postburn and normal at 7 d postburn. These results warrant pharmacokinetic studies in human burn patients.

Effect of cimetidine on the pharmacokinetics of quinidine and lidocaine in the rat.

Because of previously reported drug interactions involving cimetidine and liver-metabolized drugs, the intravenous pharmacokinetics of quinidine (25 mg/kg) and lidocaine (15 mg/kg) were investigated in anesthetized rats pretreated with a single intraperitoneal dose of cimetidine (60 mg/kg) and compared with saline pretreated controls. Significant reductions of 35 and 23% in the respective total clearances of quinidine and lidocaine were observed in the presence of cimetidine. The quinidine volume of distribution was significantly decreased in the cimetidine-treated rats, while the lidocaine volume of distribution was not altered significantly. There was no significant change in the elimination half-life for either drug in the presence of cimetidine. These results suggest cautious use of quinidine or lidocaine when cimetidine is prescribed concurrently.

Effect of renal failure or biliary stasis on the pharmacokinetics of amiodarone in the rat.

The single dose intravenous pharmacokinetics of amiodarone (50 mg/kg) were examined in rats with 72 h of biliary stasis secondary to bile duct ligation compared with paired control animals; and in rats with uranyl nitrate induced acute renal failure compared with paired control animals. Plasma and tissue levels (liver, kidney, heart, and lung) of amiodarone (1) and its N-deethyl metabolite 2 were obtained at 4 and 24 h following drug administration. Pharmacokinetic parameters were derived from plasma samples obtained over a 24-h period. Compared with controls, biliary stasis caused a decrease in the total clearance of 1 (1.74 versus 0.35 L/h/kg) and in the volume of distribution at steady state (21.1 versus 5.0 L/kg); renal failure caused a decrease in total clearance (1.67 versus 0.9 L/h/kg) and an increase in apparent elimination half-life (13.7 versus 10.1 h). Both disease processes produced significantly higher plasma levels of 1 when compared with control animals at 4 and 24 h. However, only the cholestatic animals had consistently higher tissue levels of 1 in the face of elevated plasma levels. In normal rats, no 1 or 2 was detected in the urine after a 50 mg/kg intravenous dose of 1, and less than 0.5% of the total dose of amiodarone (1) was excreted into bile by 12 h.

Effect of phenobarbitone on the pharmacokinetics and tissue levels of amiodarone in the rat.

Phenobarbitone pretreatment has been shown to increase amiodarone total clearance and decrease amiodarone elimination half-life after a single intravenous amiodarone dose in the rat. Coadministration of phenobarbitone with amiodarone for 7 days resulted in decreased tissue amiodarone levels compared to controls. These results may have implications for patients undergoing therapy with amiodarone and concomitant potent enzyme inducing drugs.

Impaired drug-metabolizing ability in the burned rat.

Research indicating hepatic dysfunction in burn injury led us to investigate the effect of thermal injury on the rat hepatic microsomal drug-metabolizing system. Heated water was used to produce burns corresponding to 15% of the rat's total body surface area. In vitro measurements of p-nitroanisole o-demethylase and aniline hydroxylase activities were significantly depressed on days 1 and 10 postburn. Likewise, in vivo sleeping and paralysis times with pentobarbital and zoxazolamine were significantly prolonged on these same postburn days. On day 10 postburn, the burned rats had significantly decreased levels of urinary D-glucaric acid, a metabolite that correlates with drug metabolizing activity. These results raise the possibility of impaired drug metabolism in human burn victims.