Sampat M. Singhvi

Disposition of captopril in normal subjects

The disposition of Captopril, an angiotensin‐converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100‐mg tablet of 35S‐labeled drug. Average absorption parameters for unchanged Captopril in blood were Tmax 0.93 ± 0.08 hr and Cmax 800 ± 76 ng/ml. For total radioactivity in blood the values were Tmax 1.05 ± 0.08 hr and Cmax 1,580 ± 90 ng/ml (as Captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of Captopril: time, elimination half‐life (t½) of unchanged drug could not be determined. At 1 hr unchanged Captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of Captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24‐hr urine sample (66% of the dose) was 58% Captopril (38% of dose), 2% Captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).

Captopril: Pharmacology, Metabolism, and Disposition

By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent. In SHR, daily oral doses of captopril progressively lowered blood pressure; normal levels were attained by the sixth month. In all species studied, the reduction in blood pressure resulted from a reduction in total peripheral resistance; cardiac output remained unchanged or increased. In humans, captopril reduces blood pressure in patients with essential hypertension with low, normal, and high renin levels, and in patients with renovascular hypertension and hypertension associated with chronic renal failure. In hypertensive patients with high plasma renin activity, captopril apparently exerts most of its pharmacologic effects through inhibition of ACE. The means by which captopril reduces high blood pressure associated with low or normal PRA is not known, but it is clear that captopril does not act on an overactive plasma renin-angiotensin system in these cases. The antihypertensive effect of captopril is enhanced when it is given in combination with a diuretic or after salt depletion. Captopril was rapidly and well absorbed in all species tested, including man. Studies in rodents indicated that ingestion of food caused a reduction in the extent of absorption and bioavailability of captopril. Captopril and/or its metabolites were distributed extensively and rapidly throughout most tissues of normal rats; no radioactivity was detected in the brain. In vitro and in vivo, captopril formed disulfide bonds with albumin and other proteins. This binding was reversible in nature. In vitro studies in blood indicates that the disulfide dimer of captopril and mixed disulfides of captopril with L-cysteine and glutathione were formed. In intact blood cells, captopril remained in the reduced form (sulfhydryl), whereas in whole blood or plasma, captopril was converted to its disulfide dimer and other oxidative products. Biotransformation of captopril may involve both enzymatic and nonenzymatic processes.(ABSTRACT TRUNCATED AT 400 WORDS)

Renal handling of captopril: Effect of probenecid

14C‐Captopril was given intravenously to four normal subjects in a 4‐mg priming dose followed by constant intravenous infusion of 1.7 mg/hr for 3.5 hr with and without concomitant probenecid. Steady‐state levels of unchanged captopril were obtained between 1.5 and 3.5 hr. In the presence of probenecid, the average steady‐state blood levels of total radioactivity were higher (36%) than on captopril alone. Unchanged captopril levels were slightly higher (14%) in the presence of probenecid. Kinetic evaluations were carried out exclusively on data for unchanged captopril. The average total body clearance (ClT) and renal clearance (ClR) of captopril in the absence of probenecid were 775 and 388 ml/kg/hr. The corresponding values for captopril with probenecid (631 and 217 ml/kg/hr) were lower. The average ratio of ClR to ClT for captopril alone was 0.50 and fell to 0.35 in the presence of probenecid. When captopril alone was given, a minimum of 78% of the renal excretion of captopril during steady‐state could be attributed to net tubular secretion, but when captopril was given with probenecid, net tubular secretion was only 57%. The volume of distribution of captopril during steady state was not altered by probenecid. For the first 3.5 hr, cumulative renal excretion of total radioactivity with and without probenecid was 55% and 60%, but cumulative excretion of unchanged captopril was higher after captopril alone (36% of dose) than after the combination (21% of dose).

Dose proportionality of nadolol pharmacokinetics after intravenous administration to healthy subjects

SummaryTo support the increasing use of intravenous β-blockers during cardiovascular emergency and surgery, dose proportionality of pharmacokinetics of nadolol was evaluated after intravenous administration of 14C-nadolol at doses of 1, 2 and 4 mg to nine healthy volunteers. There were no observed differences in the excretion or the pharmacokinetics of nadolol with respect to the dose administered. Over a 72-h period after drug administration, an average of about 60% of the dose was excreted in the urine and about 15% was excreted in the feces. The range of values for total body clearance (219 to 250 ml·min−1), renal clearance (131 to 150 ml·min−1), mean residence time (10.5 to 11.3 h), half-life (8.8 to 9.4 h), and steady-state volume of distribution (Vss) (147 to 157 l) indicated that nadolol was extensively distributed and slowly cleared from the body. There was a linear correlation (r2=0.97) between the area under the plasma concentration of nadolol versus time curve (AUC) and the dose. All pharmacokinetics parameters, except Vss, were slightly, but significantly, different at the 4 mg dose. Superposition of the dose-normalized average concentrations indicated that despite these minor differences in parameters, the pharmacokinetic behavior of nadolol was linear with respect to dose. Urinary excretion of nadolol was dose independent.

High-performance liquid chromatographic method for the radiometric determination of [14C] bucromarone in human plasma utilizing non-radiolabeled bucromarone as an internal standard.

A novel radiometric high-performance liquid chromatographic (HPLC) method was developed for the determination of [14C]bucromarone in human plasma. The procedure involved the addition of non-radiolabeled bucromarone hydrochloride to each plasma sample as an internal standard; the plasma sample was then extracted, and the bucromarone was separated from its metabolites and endogenous compounds by reversed phase HPLC. The concentration of [14C]bucromarone in each plasma sample was calculated from the ratio of the amount of radioactivity in the eluate fraction corresponding to bucromarone and the peak height of the ultraviolet absorbance (210 nm) of the non-radiolabeled bucromarone used as an internal standard. The lower limit of quantitation for bucromarone free base in this assay was 8 ng/ml when [14C]bucromarone succinate had a specific activity of 0.5 microCi/mg. The coefficients of variation for the experimentally determined concentrations of bucromarone in spiked plasma samples were 6.8 and 14.3% at concentrations of 80 and 20 ng/ml, respectively. This method was used to determine concentrations of bucromarone in the plasma of healthy volunteers who were given intravenous infusions of [14C]bucromarone succinate. In general, the methodology should be applicable to any radiolabeled compound that possesses appreciable ultraviolet absorbance.

Pharmacokinetics of intravenous captopril in healthy men

SummaryThe pharmacokinetic characteristics of intravenously-administered captopril were investigated in 7 healthy men 20 to 33 years old. Capropril, labeled with14C, was given by injection over a 1 min period at mean doses of 2.78 mg (13.8 µCi), 5.67 mg (28.2 µCi) and 11.4 mg (56.8 µCi). Concentrations of unchanged captopril, captopril disulfide, and other metabolites (collectively) were determined in body fluids.Pharmacokinetic parameters were calculated for unchanged captopril, and it was shown that the disposition of intravenously-administered drug was linear with respect to dose over the dosage range studied.

Chapter 18 Drug Metabolism

Publisher Summary This chapter summarizes the examples of recent developments in the field of drug metabolism that may be helpful to the medicinal chemist, and may provide insight into the current state of theoretical understanding and technological advances in the field. The hemisuccinate ester has been shown to provide protection against first-pass metabolism after oral administration and has been proposed as a prodrug of propranolol The prodrug, bitolterol, and di-p-toluate ester of N-t-butylarterenol has been shown to provide longer duration of bronchodilator activity in dogs than does the parent drug. A linear relationship has been observed between the renal clearance of nadolol and the glomerular filtration rate (GFR) in dogs in different stages of experimentally-induced renal impairment. The body clearance of two other β-adrenergic blocking agents, atenolol and pindolol, has also been found to correlate with the GFR. The extent of and changes in the binding of drugs and their metabolites to plasma as well as tissue proteins can greatly affect their distribution and elimination, and may, therefore, influence the extent and duration of effect. In this chapter, the possible role of excited states of oxygen in cytochrome P-450 linked oxidations as well as in the induction of the P-450 system by many diverse compounds has also been discussed in this chapter. Because many drugs contain either chiral centers, prechiral centers, or both, interest in stereochemical substrate-enzyme interactions, the stereospecificity of biotransformations, and species (and strain) differences in these parameters is increasing. Because enzymes themselves contain chiral centers, differential interaction of R and S isomers of drugs with drug metabolizing enzymes is the rule rather than exception. The chapter concludes with the discussion of significant progress that has been made in understanding the relationship between biotransformation and toxicity of numerous drugs.