Influence of food on the pharmacokinetics of perindopril and the time course of angiotensin-converting enzyme inhibition in serum.

Food has been shown to reduce the bioavailability of the angiotensin-converting enzyme inhibitor captopril, but not the bioavailability of inhibitors administered as ester prodrugs. Perindopril is the ester pro-drug of the angiotensin-converting enzyme inhibitor perindoprilat. The influence of food on the pharmacokinetics of perindopril (4 mg administered orally) and the time course of angiotensin-converting enzyme inhibition in serum was studied in a randomized crossover short-term study of 12 healthy subjects. Food significantly decreased the relative availability of perindoprilat by 35% +/- 42%, the fractional urinary excretion of perindoprilat from 19% +/- 7% to 13% +/- 4% (p less than 0.05), and the partial metabolic clearance of perindopril to perindoprilat from 102 +/- 57 ml.min-1 to 72 +/- 32 ml.min-1 (p less than 0.05). These changes were associated with a significant decrease in the area under the percent angiotensin-converting enzyme inhibition-versus-time curve by 15% (p less than 0.05). Food did not alter the total amount of drug recovered in urine as perindopril and its metabolites, and it did not alter perindoprilat renal clearance. We concluded that food alters the conversion of perindopril to its active metabolite perindoprilat after single-dose administration of perindopril.

Pharmacokinetics of nalbuphine in infants, young healthy volunteers, and elderly patients.

Nalbuphine is a new agonist and antagonist opioid analgesic agent that undergoes an important hepatic metabolism. In this study, we compared the pharmacokinetics of intravenous and oral nalbuphine in three groups of subjects: group I consisted of 14 children from 1 1/2 to 5 years of age (group IA) and from 5 through 8 1/2 years of age (group IB), group II consisted of 9 healthy male volunteers from 23 to 32 years of age, and group III consisted of 9 elderly patients from 65 to 90 years of age. All subjects and patients had normal hepatic and renal functions. The children received an intravenous injection of nalbuphine (0.2 mg/kg), and the subjects and patients in groups II and III received, at random, 10 mg intravenous injections and 30 mg oral doses of nalbuphine on two separate occasions. The distribution of nalbuphine was not modified with age. Elimination half-life (t1/2) was significantly shorter in group I (0.9 hour) than it was in group II (1.9 hours) and in group III (2.3 hours). Systemic clearance of nalbuphine decreased significantly with age. Absolute bioavailability of nalbuphine increased from F = 12% in group II to 46.3% in group III (p less than 0.01). These findings suggest that doses and rates of administration of nalbuphine should be adapted in younger patients and in elderly patients.

Clinical pharmacology of hydroxy-3(S)-dihydroquinidine in healthy volunteers following oral administration.

Pharmacokinetics and effects of oral hydroxy-3(S)-dihydroquinidine (3-OH-HQ) on heart rate (HR), blood pressure (BP), and ECG intervals were studied in 12 healthy volunteers. Three oral single doses of 3-OH-HQ (225, 450, and 900 mg) and placebo were randomly administered to each subject at one week intervals. Pharmacokinetics of 3-OH-HQ was linear in the range of administered doses, with rapid absorption (tmax 0.5-2.5 h) and distribution (t1/2 alpha 0.8-1.2 h) phases. Elimination half-lives did not significantly change with the three doses (15 +/- 4.3, 13.7 +/- 3.9, and 13 +/- 2.2 h). Unchanged 3-OH-HQ was partially eliminated by urine (mean renal clearance 0.24 +/- 0.02 L h-1 kg-1). 3-OH-HQ significantly increased HR after the three doses as compared to placebo. PR interval was not significantly modified but QRS duration significantly increased from 91 +/- 7 to 108 +/- 11 ms (p less than 0.001) 2 h after the 900 mg dose. QTc interval was significantly prolonged from 0.5 to 8 h after the highest dose (14.4 +/- 8.7% 1 h after dosing). Heart rate QRS, and QTc variations were significantly correlated to 3-OH-HQ plasma levels.