Ashok Rakhit

Pharmacokinetics and Pharmacodynamics of Pentopril, a New Angiotensin-Converting-Enzyme Inhibitor in Humans

In a single, ascending‐dose tolerance study, nine healthy volunteers were given oral pentopril 50 to 750 mg (CGS 13945) in groups of three each. Disposition characteristics of pentopril and its active metabolite (CGS 13934) were determined using plasma concentration and urinary excretion data. The drug was absorbed rapidly following zero‐order kinetics. The drug has an apparent volume of distribution of 0.83 L/kg and an oral clearance of about 0.79 L/hr/kg. Urinary excretions, calculated after 125‐ and 250‐mg doses, showed a dose proportional urinary recovery of 21% (±5%) for pentopril and 40% (±5%) for CGS 13934. In the multiple‐dose study of 125 mg orally q12h in six healthy subjects, the plasma concentrations for both drug and metabolite showed no appreciable accumulation of either compound, which was expected from their short pharmacokinetic half‐lives (pentopril, <1 hr; CGS 13934, ∼2 hr). In a separate pharmacodynamic study, drug and metabolite concentrations were evaluated against angiotensin‐I (AI)‐induced changes in blood pressure and plasma angiotensin‐converting‐enzyme (ACE) activity in healthy volunteers after single oral doses (range, 10–500 mg). The pharmacodynamic half‐life for plasma ACE inhibition increased with the dose (10 mg, 1.5 hr; 500 mg, 9.8 hr). There was a close relationship between the plasma level of the metabolite and the inhibition of plasma ACE activity and AI‐induced pressor response. A hyperbolic function adequately described the dependence of plasma ACE activity on plasma metabolite concentration with a concentration at half‐maximal inhibition of 53 ng/mL.

Pharmacokinetics of quinidine and three of its metabolites in man

Disposition parameters of quinidine and three of its metabolites, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9±(SD) 0.3 mg/L were: 3-hydroxy quinidine, 0.32±0.06 mg/L; quinidine N-oxide, 0.28±0.03 mg/L; and quinidine 10,11-dihydrodiol, 0.13±0.04 mg/L. Plasma trough levels after 12 oral doses of quinidine sulfate every 4 hr averaged: quinidine, 2.89±0.50 mg/L; 3-hydroxy quinidine, 0.83±0.36 mg/L; quinidine N-oxide, 0.40±0.13 mg/L; and quinidine 10,11-dihydrodiol, 0.38±0.08 mg/L. Relatively higher plasma concentrations of 3-hydroxy quinidine metabolite after oral dosing probably reflect first-pass formation of this quinidine metabolite. A two-compartment model for quinidine and a one-compartment model for each of the metabolites described the plasma concentration-time curves after both i.v. infusion and multiple oral doses. Mean (±SD) disposition parameters for quinidine from individual fits, after i.v. infusion were as follows: V1,0.37±0.09 L/kg; λ1,0.094±0.009 min−1; λ2, 0.0015±0.0002 min−1; EX2, 0.013±0.002 min−1;clearance (ClQ),3.86±0.83 ml/min/kg. Both plasma and urinary data were used to determine metabolic disposition parameters. Mean (±SD) values for the metabolites after i.v. quinidine infusion were as follows: 3-hydroxy quinidine: formation rate constant kmf,0.0012±0.0005 min−1,volume of distribution, Vm,0.99±0.47 L/kg; and elimination rate constant, kmu0.0030±0.0002 min−1.Quinidine N-oxide: kmf,0.00012±0.00003 min−1; Vm,0.068±0.020 L/kg; and kmu,0.0063±0.0008 min−1.Quinidine 10,11-dihydrodiol: kmf,0.0003±0.0001 min−1; Vm,0.43±0.29 L/kg; and kmu,0.0059±0.0010 min−1.Oral absorption of quinidine was described by a zero order process with a bioavailability of 0.78. Concentration dependent renal elimination of 3-hydroxy quinidine was observed in two out of five subjects studied.

Inhibition of renal clearance of furosemide by pentopril, an angiotensin-converting enzyme inhibitor.

The pharmacokinetic interaction between pentopril (250 mg) and furosemide (40 mg) was studied in 12 normal healthy volunteers after oral administration of each drug alone and in combination. No significant changes in any pharmacokinetic parameters of pentopril or its active metabolite (CGS 13934) were observed on coadministration of furosemide. In contrast, pentopril induced significant changes in disposition of furosemide. Pentopril decreased renal clearance (CLR) of furosemide by 54% and the fraction excreted unchanged in urine also decreased by 55%. However, such decrease in CLR of furosemide was compensated by a simultaneous increase in glucuronidation (by 200%), resulting in a slight increase in systemic clearance (decreased AUC). Systemic bioavailability of furosemide appears to be unchanged in the presence of pentopril (0.46 vs. 0.41). No effect of pentopril on plasma protein binding of furosemide was detected. In spite of the decreased CLR and urinary excretion rate of furosemide, the urinary output (1749 vs. 1774 ml/6 hr) and Na+ excretion (757 vs. 816 mEq/6 hr) remained almost unchanged. These findings suggest that total furosemide (unchanged and glucuronide) might contribute to diuresis and natriuresis rather than the unchanged furosemide alone. Because of unchanged pharmacodynamic effect, such pharmacokinetic interaction may not require any dosage adjustment for furosemide on pentopril coadministration.

Increased blood-brain barrier permeability of amino acids in chronic hypertension

A previous communication from this laboratory reported that brain uptake of libenzapril, a small polar molecule, was enhanced in chronic hypertension (1). The objective of this investigation was to determine if this was a more generalized phenomenon. Therefore, experiments were undertaken to examine the effect of chronic hypertension on the brain uptake of tryptophan (an amino acid with high brain permeability) and glutamic acid (one with low permeability). Brain concentrations of these two amino acids were 5- to 12-fold greater in chronic hypertensive rats, as compared to normotensive rats; the corresponding brain uptake index (BUI) values were 2- to 5-fold higher in the former group. Since blood-brain barrier transport of amino acids involve both saturable (carrier) and non-saturable (most likely, diffusion via pores) mechanisms, data from this study show that hypertension can enhance BBB transport of amino acids by affecting one or both of these pathways.

Gastroscopic localization of a microencapsulated KCI preparation in the human stomach

A slow release polymer-coated preparation of potassium chloride granules (Micro-K Extencaps) was initially thought not to be associated with gastric mucosal damage. Recent studies have shown that acute gastric ulcers occur with approximately the same frequency as in patients taking wax matrix KCl formulations. The development of acute gastric ulcers was not consistent with the proposed dispersion characteristics of the microencapsulated KCl preparation. The authors therefore endoscopically evaluated the dispersion characteristics of microencapsulated KCl in a double-blind, placebo-controlled study. Subjects received four capsules of Micro-K or matching placebo and endoscopy was performed 30, 60, or 120 min after each drug ingestion. The material was identified with the Olympus HM (high magnification) endoscope and then quantitatively aspirated using the 3.5-mm biopsy channel of the Pentax 34JA endoscope. Microencapsulated KCl particles dispersed poorly and were found adhering to the mucosa and to one another, as a semisolid mass, most frequently in the gastric antrum. In contrast, the placebo (ethyl cellulose) was widely dispersed throughout the stomach. The authors concluded that gastric emptying must be considered in three phases: liquids, solids, and solids which adhere to the mucosa. No unique dispersion characteristics of Micro-K Extencaps were identified, and adherence of the KCl to the gastric mucosa may explain its ability to cause occasional acute gastric ulceration.

Pentopril-Cimetidine Interaction Caused by a Reduction in Hepatic Blood Flow

The interactive effects of the coadministration of steady‐state Cimetidine and single‐dose pentopril, an angiotensin converting enzyme inhibitor, on the pharmacokinetic disposition of each other were studied in humans. Cimetidine reduced the clearance of pentopril by 11 to 14%. This reduction in clearance was shown to be caused by a reduction in liver blood flow probably mediated through H2 receptor blockade. Meanwhile pentopril induced the oral clearance of Cimetidine by 21%, presumably by a reduction in the bioavailable fraction of Cimetidine. The mechanism of this interaction is unknown.

Kinetics of potassium excretion following oral supplements: evidence of induced natriuresis

Twenty-four healthy normal volunteers were given 40 mEq of three oral formulations of K+ as potassium chloride in a three-way Latin square design. Pharmacokinetic characteristics of potassium disposition were determined using urinary excretion data. Potassium was absorbed almost instantaneously from the 10% (w/v) solution, while a slow first-order absorption could explain the slow release of potassium from Slow-K and the new slow-release tablet. A biphasic elimination of potassium observed during the first 24 hr of urinary excretion suggested the bodys adaptive process of changes in rates of elimination of potassium to maintain homeostasis. There was no significant difference (P = 0.25) in total recoveries of potassium in urine during 48 hr of urinary collection among the three formulations (mean ± SE: solution, 35 ± 7.1 mEq; Slow-K, 38.1 ± 7.8 mEq; and new formulations, 33.5 ± 6.8 mEq). An increased excretion of sodium was observed and correlated with increased potassium excretion following oral potassium administration which could not be explained by changes in urine flow rate. The clinical significance of such an increase in natriuresis is yet to be determined.

Effects of Food on the Bioavailability of CGS 16617, an Angiotensin‐Converting Enzyme Inhibitor, in Healthy Subjects

Pentopril (CGS 13945) was administered in 125‐mg capsules to eight healthy men on two occasions according to a randomized schedule; on one occasion in the fasting state and on the other occasion immediately following the ingestion of a standardized meal. Unlike captopril, a prototype angiotensin‐converting‐enzyme inhibitor, there was no significant difference in the peak plasma concentration for either the drug or its active metabolite (CGS 13934) between the fasting and the fed states. There was also no appreciable change in the area under the plasma curve for the drug and its metabolite after administration of drug in the presence of food compared with a fasting state. There was, however, a lag time in drug absorption after ingestion of food, which resulted in a significant increase in peak time for the active metabolite in plasma. Food delays the bodys absorption of the drug and hence the appearance of its active metabolite in plasma without any significant effect on the relative bioavailability. Because relative bioavailability is not affected in the presence of food, such a delay may not have any therapeutic importance on chronic administration.

Induction of quinidine metabolism and plasma protein binding by phenobarbital in dogs

Two porta-caval transposed mongrel dogs were studied for phenobarbital (PB) induction of quinidine disposition after separate quinidine infusions via normal intravenous route and via portal vein. The plasma concentrations of quinidine and of three metabolites measured (3-OH quinidine, quinidine N-oxide, quinidine 10,11-dihydrodiol) were quite similar between i.v. and portal vein infusions, suggesting that the liver extraction ratio for quinidine in dogs is very low. After PB pretreatment plasma quinidine concentrations at the end of a 10 hr infusion increased about two-fold while the half-life decreased from a control value of about 16 hr to 6 hr. Plasma concentrations of the three major metabolites measured were also increased following PB treatment. Plasma protein binding for quinidine and two of its three measured metabolites (3-hydroxy quinidine and quinidine N-oxide) were increased after PB treatment. Pharmacokinetic analysis of the data showed a decrease in steady-state volume of distribution (Vdss)of quinidine from an average value of 153 L to 54 L after PB treatment, while the total clearance did not change (6.6 vs. 5.6L/hr). This decrease in Vdsscould be explained by an increase in plasma protein binding of quinidine after PB treatment. The unbound nonrenal clearance of quinidine was induced by PB treatment. The decrease in fraction free in plasma and increase in unbound nonrenal (hence total) clearance resulted in little or no change in total plasma clearance for quinidine. The formation rate constants calculated for two quinidine metabolites, 3-hydroxy quinidine and quinidine N-oxide, were increased after PB treatment, suggesting an induction in these two metabolic pathways. Only quinidine 10,11-dihydrodiol was found in the bile after quinidine infusion, and the biliary clearance of this metabolite was also induced after PB treatment.

Pharmacokinetics and pharmacodynamics of quinidine and its metabolite, quinidine-N-oxide, in beagle dogs

SummaryQuinidine and one of its major metabolites, quinidine-N-oxide, were given by separate i.v. infusions to each of three beagle dogs. Plasma and urine samples were analysed for pharmacokinetic comparison of the drug and its metabolite. Quinidine apparently distributed into two major compartments, while the N-oxide distributed into three compartments. The compartment-independent pharmacokinetic parameters (mean ± SD) were for quinidine Vdss 4.78±1.1 l/kg, clearance 0.074±0.047 l/min, terminal half-life 720±343 min and for quinidine-N-oxide Vdss 1.03±0.21 l/kg, clearance 0.065±0.012 l/min, terminal half-life 316±69 min. Only 29% of quinidine was recovered in the urine as unchanged drug while 77% of the N-oxide was excreted unchanged via the kidney. Non-linear renal elimination of the N-oxide was observed in two out of three dogs with a Michaelis-Menten constant, KM of about 7 μg/ml (21 μM).Prolongation of the QT-interval in the ECG response was used for comparing pharmacodynamic effects. Quinidine was about three to four fold more active than the N-oxide at similar plasma concentrations. Quinidine-N-oxide concentrations in plasma after quinidine administration were very low and would not contribute significantly to the quinidine effect.