Biomedical subjects

S M Singhvi

Publications and source records attributed to S M Singhvi.

At least 19 recordsLinked to original sources

PubMed1990

Disposition of zofenopril calcium in healthy subjects.

Zofenopril calcium (1) is a prodrug that is hydrolyzed in vivo to the active angiotensin-converting enzyme (ACE) inhibitor SQ 26,333 (2). In a two-way crossover study, six healthy male subjects (age range 25-36 years) each received an iv 11.2-mg dose of [14C]SQ 26,703 (14C-3; the L-arginine salt of 2) and an oral 10-mg (equimolar) dose of 14C-1. After the iv dose of 14C-3, the 0-96-h recovery of radioactivity averaged 76 and 16% of the dose in urine and feces, respectively, indicating substantial biliary secretion. After the oral dose of 14C-1, excretion of radioactivity averaged 70% (urine) and 26% (feces). Negligible amounts of 1 were present in urine, indicating complete hydrolysis of the orally administered prodrug. The oral absorption of 1 was almost complete and the oral bioavailability of 2 averaged approximately 70%. The terminal elimination half-life for 2 after the iv dose averaged 5.5 h. Whole body clearance, renal clearance, nonrenal clearance, and Vdss averaged 11.4, 3.1, and 8.3 mL/min/kg and 1.3 L/kg, respectively. These data indicated that 2 is eliminated by the kidney as well as the liver, is extensively metabolized, and is distributed extensively into extravascular sites.

Administration, Oral↗

PubMed1990

Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects.

Pravastatin sodium, a competitive inhibitor of HMG-CoA reductase, is a new orally effective hypocholesterolaemic agent. In a two-way crossover study, eight healthy male subjects each received an intravenous and an oral dose of [14C]-pravastatin sodium. The oral absorption of [14C] activity from pravastatin sodium was about 34% and the oral bioavailability was about 18%, suggesting first-pass metabolism of pravastatin. After the intravenous dose, the recovery of radioactivity averaged 60% and 34% in urine and faeces, respectively. Corresponding values were 20% (urine) and 71% (faeces) for the oral dose. The estimated average plasma elimination half-life of pravastatin was 0.8 and 1.8 h for the intravenous and oral routes, respectively. The average values for total and renal clearances were 13.5 and 6.3 ml min-1 kg-1, respectively, and the steady-state volume of distribution averaged 0.51 kg-1. These results suggest that both kidney and liver are important sites of elimination for pravastatin.

Administration, Oral↗

PubMed1989

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.

Anti-Arrhythmia Agents↗

PubMed1988

Dose proportionality of nadolol pharmacokinetics after intravenous administration to healthy subjects.

To support the increasing use of intravenous beta-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.

Adult↗

PubMed1988

Pharmacokinetics of intravenous captopril in healthy men.

The pharmacokinetic characteristics of intravenously-administered captopril were investigated in 7 healthy men 20 to 33 years old. Capropril, labeled with 14C, was given by injection over a 1 min period at mean doses of 2.78 mg (13.8 microCi), 5.67 mg (28.2 microCi) and 11.4 mg (56.8 microCi). 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.

Adult↗

PubMed1988

Disposition of fosinopril sodium in healthy subjects.

1 Fosinopril sodium is the first phosphorus-containing angiotensin-converting enzyme (ACE) inhibitor to be studied clinically as an antihypertensive agent. It is an ester prodrug that is hydrolysed in vivo to the active diacid ACE inhibitor, SQ 27, 519. 2 In a three-way crossover study, nine healthy male subjects (age range 20-34 years) each received an intravenous 7.5 mg dose of SQ 27, 519-[14C] and two oral 10 mg doses of [14C]-fosinopril sodium, administered as a capsule and in solution. 3 After the intravenous dose of SQ 27, 519, the 0 to 96 h recovery of radioactivity averaged 44 and 46% of the dose in urine and faeces, respectively, indicating substantial biliary secretion. Only intact SQ 27, 519 was detected in the plasma, urine, and faeces following the intravenous dose of SQ 27, 519. 4 After oral doses of fosinopril sodium, about 75% of the radioactivity in plasma and urine was present as SQ 27, 519; the remainder corresponded mainly to a beta-glucuronide conjugate of SQ 27, 519 (15-20%), and a monohydroxylated analogue of SQ 27, 519 (about 5%). Negligible amounts of fosinopril sodium were present, indicating complete hydrolysis of the prodrug. 5 For the solution and capsule doses, respectively, the oral absorption of fosinopril sodium averaged 32% and 36% and the oral bioavailability of SQ 27, 519 averaged 25% and 29%. 6 The average values for clearance (39 ml min-1), renal clearance (17 ml min-1), Vss (10 1), and plasma protein binding (approximately 95%), indicated that SQ 27, 519 was slowly cleared from the body and not distributed extensively into extravascular sites.

Administration, Oral↗

PubMed1987

Relationship between metabolism and pharmacologic activity of SQ 27,786, an angiotensin converting enzyme inhibitor with potent diuretic activity.

SQ 27,786 is a sulfhydryl-containing angiotensin converting enzyme (ACE) inhibitor, which also possesses potent diuretic activity in dogs after intravenous administration. The absorption, distribution, metabolism and elimination of 35S-labeled SQ 27,786 was studied in dogs to determine if the observed pharmacologic activities were intrinsic to this compound or the result of metabolism to separate ACE-inhibitory and diuretic moieties. The poor pharmacologic activity observed after oral administration was found to be due to poor absorption of the ACE-inhibitory-diuretic compound. The results of this study indicated that SQ 27,786 was excreted largely intact, either as the parent compound, the symmetrical disulfide of the parent compound, or as mixed disulfides of the parent compound with endogenous sulfhydryl compounds (e.g., SQ 27,786-L-cysteine) in a manner similar to captopril. It was concluded that the observed diuretic and ACE inhibitory activities were the result of intact SQ 27,786 and not of metabolites resulting from cleavage of the molecule to separate diuretic and ACE inhibitory moieties.

Angiotensin II↗

PubMed1985

Application of pharmacokinetics in drug safety evaluation.

The discipline of pharmacokinetics plays an important role in safety evaluation of drugs. In this presentation various kinds of pharmacokinetic studies have been discussed with specific examples of the studies that should be conducted in support of safety evaluation of new drugs. The design and evaluation of toxicologic and pathologic studies in animals, as well as of safety and efficacy studies in man, should take into consideration the pharmacokinetic characteristics of drugs.

Animals↗

PubMed1985

Tissue distribution of 14C- and 35S-captopril in rats after intravenous and oral administration.

35S-Captopril (50 mg/kg) administered i.v. to rats resulted in radioactivity being widely distributed into highly vascular tissues and into excretory organs. After oral administration of 14C-captopril (50 mg/kg), radioactivity in most tissues declined at a rate similar to that in blood. Concn. greater than those in blood were found only in kidney, liver and lung. The high concn. of 14C in kidney and liver were due to the excretory role of these organs. The high concn. of 14C in lung may be due to the high binding affinity of captopril to angiotensin-converting enzyme, present in large quantity in lung.

Administration, Oral↗

PubMed1984

Quantitative determination of captopril in blood and captopril and its disulfide metabolites in plasma by gas chromatography.

A sensitive, quantitative gas chromatographic-electron capture (GC-EC) method for the determination of captopril in blood and captopril and its disulfide metabolites (collectively) in plasma was developed. After addition of an internal standard and N-ethylmaleimide to the biological samples, excess N-ethylmaleimide and naturally occurring interfering substances were removed by extraction with benzene followed by acidification and extraction with hexane. The N-ethylmaleimide adducts of captopril and of the internal standard were then extracted with benzene and converted to their hexafluoroisopropyl esters. For the assay of captopril and its disulfide metabolites, tributylphosphine was used to reduce the disulfide metabolites to captopril prior to derivatization. The hexafluoroisopropyl esters of the N-ethylmaleimide adducts of captopril and of the internal standard, the 4-ethoxyproline analogue of captopril, were separated by GC on a column packed with 3% OV-101 on Chromosorb W-HP. The lower limits of sensitivity were 20 ng/mL for captopril in blood and 50 ng/mL for captopril and its disulfide metabolites in plasma. Linearity, precision, and accuracy were excellent. The method was validated by comparison of results obtained for total captopril in dog plasma by the GC-EC assay with results obtained by a published GC-MS method. The assay was applied to dog and human samples to explore its general utility.

Administration, Oral↗

PubMed1984

Elimination kinetics of captopril in patients with renal failure.

Captopril kinetics were determined after a 100-mg oral dose of 14C-captopril in 21 patients with various degrees of renal impairment. Elimination kinetics of captopril were evaluated by model-independent methods. The body clearance (ClB) of captopril decreased steadily with decreasing creatinine clearance (ClCr) from 5.2 ml/min/kg for mild renal failure patients to 1.6 ml/min/kg for hemodialysis patients during an interdialytic period. In patients with mild renal impairment, renal and nonrenal clearances of captopril averaged 2.2 and 3.0 ml/min/kg, respectively, and fell (P less than 0.001) to 0.2 and 1.5 ml/min/kg in patients with severe renal impairment. There were no significant differences in the extent of total cumulative excretion (fecal plus urinary) of radioactivity over a 96- to 120-hr period between the patients with mild, moderate, and severe renal impairment. The 48-hr renal excretion of captopril averaged 29, 21, and 8% of the dose in the mild, moderate, and severe renally impaired groups. In five additional hemodialysis patients, the mean dialyzer clearance of captopril averaged 120 ml/min. Approximately 35% of the dose was recovered in the 4-hr dialysate. Based on the above findings, a reduction in the dose of captopril is necessary in patients with renal failure.

Adult↗

PubMed1984

Disposition of [14C]aztreonam in rats, dogs, and monkeys.

[14C]aztreonam was administered as single 25-mg/kg doses to dogs (intravenously and subcutaneously) and monkeys (intramuscularly and intravenously) and as single 50-mg/kg doses (intramuscularly and intravenously) to rats. In rats and dogs, radioactive moieties were excreted primarily in urine; in monkeys, they were excreted about equally in urine and feces. Unchanged aztreonam accounted for 77 to 86% of the radioactivity excreted in the urine of rats, dogs, and monkeys; SQ 26,992, the metabolite resulting from hydrolysis of the monobactam ring, accounted for 10 to 15%; and minor, unidentified metabolites accounted for the remainder. In rats with cannulated bile ducts, about 15% of an intramuscular dose was excreted in bile in 24 h; the bile contained a greater percentage of metabolites than that found in urine. In dogs, the apparent elimination half-life of aztreonam in serum was 0.7 h after intravenous administration. Aztreonam and SQ 26,992 accounted for most of the radioactivity in the sera of dogs and monkeys. Serum protein binding of aztreonam and its metabolites ranged from 28 to 35% in dogs and from 49 to 59% in monkeys. In the three species studied, aztreonam was most extensively metabolized in monkeys; SQ 26,992 and other minor metabolites from monkey urine were tested and found to be devoid of any significant antimicrobial activity.

Animals↗

PubMed1984

Distribution of [14C]aztreonam in rat tissue.

[14C]aztreonam was administered intramuscularly (50 mg/kg) to male and female rats. Groups of 10 rats (five male and five female) were sacrificed at 0.25, 2, 6, and 24 h after dosing. Blood and various tissues were removed from six rats (three male and three female) in each group for determination of total radioactivity and unchanged aztreonam by liquid scintillation counting and thin-layer radiochromatography. The remaining rats were prepared for whole-body autoradiography. Radioactivity was distributed rapidly to most tissues and was rapidly eliminated from blood into urine and bile. Concentrations of total radioactivity in kidney, liver, small and large intestines and their contents, and urinary bladder were higher than those in serum at all the times examined. Concentrations of unchanged aztreonam in serum, kidney, liver, and lung declined at about the same rate as did that of total radioactivity in the same tissues. The results of whole-body autoradiography essentially confirmed the results of the distribution of [14C]aztreonam as determined by liquid scintillation counting. No major differences between males and females were observed when concentrations in organs common to both were compared.

Animals↗

PubMed1984

Distribution of aztreonam into fetuses and milk of rats.

Subcutaneous administration of [14C]aztreonam (150 mg/kg) to pregnant rats was followed by the appearance of radioactive moieties in fetuses and amniotic fluid. Concentrations of both total radioactivity and unchanged aztreonam in maternal serum declined more rapidly than those in fetuses and amniotic fluid. [14C]aztreonam (150 mg/kg) was also administered subcutaneously to lactating rats. Radioactivity and unchanged aztreonam were found in the suckling pups and in the serum and milk of the dam. Results obtained by whole-body autoradiography were generally consistent with these obtained by measuring radioactivity present in the excised tissues. Autoradiographs of the pups showed detectable amounts of radioactivity in the brain; since no radioactivity was detectable in the brain of the dam, it appears that the blood-brain barrier was not fully developed in 7-day-old pups.

Amniotic Fluid↗

PubMed1984

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)

Animals↗

PubMed1983

Metabolism and pharmacokinetics of aztreonam in healthy subjects.

The metabolism and pharmacokinetics of aztreonam (SQ 26,776) were studied in four healthy male volunteers, each of whom received single 500-mg intravenous and intramuscular doses of 14C-labeled drug according to a two-way crossover design. Serial samples of serum, urine, and feces were assayed for aztreonam and metabolites. Serum pharmacokinetics of aztreonam administered intravenously were described by an open, linear, two-compartment kinetic model. Kinetics of intramuscular aztreonam followed a one-compartment model with first-order absorption and elimination. Intramuscular bioavailability was 100%. After either intravenous or intramuscular administration, aztreonam was eliminated primarily by urinary excretion of unchanged drug (about 66% of dose), whereas only 1% of the dose was found as unchanged drug in the feces, presumably owing to biliary secretion. The average elimination half-life of aztreonam was 1.6 and 1.7 h, respectively, for intravenous and intramuscular administration. Aztreonam did not undergo extensive metabolism; the most prominent biotransformation product of aztreonam was SQ 26,992, the compound resulting from the hydrolytic opening of the beta-lactam ring. Urinary and fecal SQ 26,992 constituted 7 and 3% of the administered dose, respectively. SQ 26,992 was eliminated at a considerably slower rate than was aztreonam.

Adult↗

PubMed1982

Captopril kinetics.

Captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was given by mouth and intravenously in 10-mg doses to five healthy subjects. After intravenous dosing, semilogarithmic plots of captopril blood levels : time showed a triexponential decay. Data were analyzed using an open three-compartment model. The average volume of distribution (Vd) was 0.2 l/kg for the central compartment and 2 l/kg for the elimination (beta) phase. The Vd at steady-state was 0.7 l/kg. The total body clearance of captopril averaged 0.8 l/kg/hr and the mean blood half-life during the beta phase was 1.9 hr. In the 0- to 96-hr urine, after intravenous and oral drug, excretion of radioactivity accounted for 87% and 61% of dose. In the 0- to 24-hr urine, averages of 38% (intravenous) and 24% (oral) of the doses were excreted as unchanged captopril. Absolute absorption of the radioactive oral dose was 71% and the absolute oral bioavailability of captopril was 62%.

Absorption↗

PubMed1982

Distribution of captopril to foetuses and milk of rats.

1. 14C-Captopril (50 mg/kg) administered orally to pregnant rats resulted in radioactivity passing the placental barrier into foetuses and amniotic fluid. Two hours after dosing, the mean (+/- S.E.M.) concentration of total radioactivity was 0.97 +/- 0.07 micrograms equiv. of captopril/g in foetuses and 7.8 +/- 0.54 micrograms equiv./g in maternal blood. The mean concentration of unchanged captopril at this time was 0.22 +/- 0.04 micrograms/g in foetuses and 2.4 +/- 0.27 micrograms/g in maternal blood. Results obtained by whole-body autoradiography generally were consistent with those obtained by measuring radioactivity in excised tissues. 2. Radioactivity was also found in suckling pups and in the milk of th dams. Autoradiographs of the pups showed detectable radioactivity in the brain; as no radioactivity was detectable in the brain of the dam, it appears that the blood-brain barrier was not fully developed in seven-day-old pups.

Animals↗