Prediction of in vivo drug interactions with eplerenone in man from in vitro metabolic inhibition data.

1: The inhibition kinetics of eplerenone (EP) 6beta-hydroxylation by 10 drugs were determined in vitro using human liver microsomes. Inhibition factors were calculated from in vitro inhibition constant (Ki) and three different inhibitor Cmax values (liver Cmax of total and unbound inhibitor, and maximum influx concentration of inhibitor into the liver). Subsequently, the inhibition factors were compared with available pharmacokinetic data derived from clinical interaction trials conducted by Pfizer involving EP and these drugs. EP was also evaluated for its effect on the metabolism of 10 drugs in vitro, and again the in vitro data were compared with results from the clinical trials. 2: The Ki values for the inhibition of EP 6beta-hydroxylation by cisapride, cyclosporine, digoxin, erythromycin, fluconazole, ketoconazole, midazolam, saquinavir, simvastatin and verapamil were 2.90, 1.24,>75.0, 9.50, 59.0, 0.160, 8.10, 0.546, 6.23 and 13.3 microM, respectively. Among the three methods, inhibition factors (Rb) calculated using the Ki and estimated liver Cmax values of the unbound drug were best correlated with the in vivo area under the curve-fold increases of EP in humans. The Rb values for the drugs listed above were 1.04, 1.69, 1.00, 2.17, 2.24, 4.90, 1.00, 1.82, 1.01 and 1.04, respectively, and the in vivo area under the curve-fold increases of EP by these drugs were 1.04, 1.16, 0.930, 2.87, 2.24, 5.39, 1.00, 2.07, 1.03 and 1.98, respectively. 3: EP did not have any significant effects on the drugs tested in vitro or in the clinic. 4: Using in vitro metabolic interaction data, human in vivo pharmacokinetic interactions involving EP could be predicted nearly quantitatively. The lack of effects of EP on the pharmacokinetics of other drugs in man was also suggested in the in vitro data.

Single- and repeated-dose pharmacokinetics of eplerenone, a selective aldosterone receptor blocker, in rats.

1. The pharmacokinetics of eplerenone (EP) were examined in rats following single or repeated dosing with (14)C-labelled or unlabelled EP to characterize absorption, metabolism and excretion. Rates of EP metabolism and cytochrome P450 activities were determined in vitro after repeated dose administration of EP. 2. Following a single i.v. dose (15 mg kg(-1)), the elimination half-life of EP was 0.80 and 1.14 h in male and female rats, respectively. Plasma clearances (CL) of EP were 1.62 and 1.20 l kg(-1) h(-1) in males and females, respectively. Following a single oral dose (15 mg kg(-1)), C(max) and T(max) of EP were 1.71 micro g ml(-1) and 0.5 h in male rats. The corresponding values in female rats were 3.54 micro g ml(-1) and 1.0 h. The systemic availability of EP was 25.6% in male rats and 66.4% in female rats, demonstrating sex differences in the pharmacokinetics of EP. 3. In the 8-day study, the AUC(0-24h)'s of total EP (closed lactone ring form plus open form) following 100 and 200 mg kg(-1) oral doses were approximately half those on day 1 in male rats. After repeated dosing for 13 weeks, the pharmacokinetics of total EP did not change with study duration at the 20 mg kg(-1) dose in both males and females. However, at the 100 mg kg(-1) dose, AUC(0-24h)'s were notably reduced on day 24 but progressively increased on subsequent days to approximate day 1 levels by day 86 in both sexes. At the 500 mg kg(-1) dose, the AUCs on day 86 remained lower than those on day 1. Reductions in AUCs on days 8 and 24 appeared to be the result of metabolism induction. 4. EP was extensively metabolized in male rats and most faecal and urinary radioactivity was in the form of metabolites. In female rats, the vast majority of urine and faecal radioactivity was associated with total EP. Thus, the sex difference in the pharmakokinetics of EP was due to more extensive metabolism in male rats. 5. The major metabolite in the rat was 6beta-OH EP. EP 6beta-hydroxylase activity was well correlated with testosterone 6beta-hydroxylase activity, indicating that EP metabolism to 6beta-OH EP was mediated primarily by CYP3A in the rat. 6. After repeated dose administration, EP increased 6beta-hydroxylase activities of testosterone and EP itself in a dose-dependent manner in both male and female rats, indicating that EP was a CYP3A inducer in the rat. There appeared to be no effects on activities of CYP1A1, 2B and 2E1.

Eplerenone: a selective aldosterone receptor antagonist (SARA).

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT(1)) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels--a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone--the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs)--is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

Morphology and immunohistochemistry of spontaneous chronic corneal epithelial defects (SCCED) in dogs.

PURPOSE: To determine the morphologic features of the epithelium and extracellular matrix in spontaneous chronic corneal epithelial defects (SCCED) in dogs. METHODS: Forty-eight superficial keratectomy specimens were obtained after confirmation of the presence of a superficial corneal erosion for longer than 3 weeks with no discernible underlying cause. Histologic samples were examined by light microscopy, scanning electron microscopy, and transmission electron microscopy. Immunolocalization of laminin, collagen IV, fibronectin, and collagen VII was performed. RESULTS: Epithelial cells adjacent to the defect were poorly attached to the underlying extracellular matrix. A prominent superficial stromal hyaline acellular zone composed of collagen fibrils in the area of the erosion was present in most specimens. Samples exhibited a varying degree of fibroplasia, vascularization, and leukocytic infiltrate. Laminin, collagen IV, and collagen VII were usually either not present or were present only in discontinuous segments on the surface of the erosion. Fibronectin usually coated the surface of the erosion, either as a continuous sheet or in discontinuous segments. Transmission electron microscopy of 15 samples revealed that the basement membrane was either absent in the area of the erosion or was present only in discontinuous segments. Scanning electron microscopy of eight of nine samples confirmed the absence of continuous basement membrane. Epithelial and extracellular matrix components in the peripheral cornea appeared normal. CONCLUSIONS: Most canine patients with spontaneous chronic corneal epithelial defects do not have a normal basement membrane structure in the region of the epithelial defect and have other abnormalities in the subjacent extracellular matrix that may reflect a part of the underlying pathophysiology of chronic and recurrent erosions.

Species difference in stereoselective involvement of CYP3A in the mono-N-dealkylation of disopyramide.

1. To determine which CYP isoenzyme is involved in the N-dealkylation of disopyramide (DP) metabolism in human and dog, and to determine the stereoselectivity of DP metabolism with human CYP and dog CYP isoenzymes, the following in vitro metabolism studies of DP were conducted: correlation between human CYP isoenzyme activities and DP metabolism with human liver microsomes; inhibition of DP metabolism in human and dog liver microsomes with chemical inhibitors of CYP isoenzymes; inhibition of DP metabolism in human microsomes with human CYP antibodies; inhibition of DP metabolism in dog liver microsomes with human and dog CYP antibodies; metabolism of DP with human (CYP3A4) and dog (CYP3A12) cDNA-expressed isoenzymes; determination of Km and Vmax of DP enantiomers by using cDNA-expressed CYP3A4 and CYP3A12. 2. In human liver microsomes, the formation of the mono-N-dealkylated disopyramide (MNDP) metabolite was best correlated with CYP3A4 activities. DP metabolism was substantially inhibited by ketoconazole, troleandomycin (TA) and human CYP3A4 antibody. DP was metabolized by cDNA-expressed CYP3A isoenzymes. In dog liver microsomes, DP metabolism was inhibited by ketoconazole, TA and dog anti-CYP3A12. DP was also metabolized by cDNA-expressed CYP3A12. 3. CYP3A4 and CYP3A12 are the principal isoenzymes involved in DP metabolism in human and dog respectively. There was no stereoselectivity in N-dealkylation of DP by human CYP3A4. However, there was notable stereoselectivity in the N-dealkylation by dog CYP3A12.

Pharmacokinetics of celecoxib after oral administration in dogs and humans: effect of food and site of absorption.

Celecoxib pharmacokinetics was evaluated after single and multiple oral dosing; after dosing in a solution and as a solid; with and without food; and after administration into different sites of the GI tract using dog. After oral dosing in a solution, celecoxib was rapidly absorbed and reached maximum concentrations by 1 h; absorption was delayed another 1 to 2 h when administered as a solid. The absolute bioavailability of celecoxib was higher when given as a solution (64--88%) compared with capsule (22--40%). The absorption of celecoxib given in a capsule was delayed by food, although systemic exposure increased by 3- to 5-fold. The systemic availability of celecoxib given intragastrically in solution was similar to that obtained following direct instillation into the duodenum, jejunum, or colon through a chronic intestinal access port. Collectively, these data suggest that celecoxib is a highly permeable drug that can be absorbed throughout the GI tract and that dissolution may be a rate-limiting factor for absorption from solid dosage forms. Unlike dogs, celecoxib given to humans with a high fat meal exhibits only a slight increase in AUC(0--infinity) (11%) that is not clinically significant with regard to safety or efficacy. In humans, a lower dose and a longer GI residence time may promote the opportunity for absorption of a poorly soluble drug such as celecoxib that can be absorbed throughout the GI tract. This would minimize the effect of food on absorption; as such, patients with arthritis can be given celecoxib with or without food.

Effect of diet and gavage on the dose- and dose-mode-dependent absorption and metabolism of bidisomide in rat.

1. The metabolism of bidisomide was investigated to examine how dose and mode of drug administration (i.e. diet admixture versus oral solution) affect the absorption and metabolism of bidisomide in the toxicity studies. 2. After dietary admixture, bidisomide was more absorbed and less metabolized at the higher doses. Reduced metabolism at the high doses resulted from saturation of stereo-specific formation of the N-desisopropyl-arylhydroxy bidisomide (NDABD) metabolite. 3. The rat-specific NDABD metabolite was formed only from (-)-bidisomide on incubation with rat liver microsomes. 4. After oral solution dosing, absorption was increased and metabolism reduced compared with the dietary admixture. 5. After 24-h infusion, plasma concentrations of radioactivity were approximately dose-proportional. However, the concentrations in the liver were similar at the 200 and 400 mg/kg doses due to saturation of liver uptake of the NDABD metabolite.

Absorption and disposition of a selective aldosterone receptor antagonist, eplerenone, in the dog.

PURPOSE: The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. METHODS: Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). RESULTS: After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. CONCLUSIONS: EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.

Congenital ocular abnormalities of Rocky Mountain Horses.

OBJECTIVE: To determine the incidence and describe ocular abnormalities in a cross-section of the population of Rocky Mountain Horses. Design: Prospective study. Animals: Five-hundred and fourteen Rocky Mountain Horses. Procedure: Ophthalmic examinations were performed using a slit-lamp biomicroscope and an indirect ophthalmoscope. Intraocular pressures were measured by applanation tonometry. Eyes from six horses were obtained for histologic examination. RESULTS: Cysts of the posterior iris, ciliary body, and peripheral retina were detected most frequently (249 horses), and were always located temporally. Curvilinear streaks of retinal pigmented epithelium extending from the peripheral temporal retina marked the boundary of previous retinal detachment in 189 horses. Retinal dysplasia was detected in 125 horses. Multiple ocular anomalies were evident in 71 horses and were always bilateral and symmetrical. Affected eyes had a large, clear cornea that protruded excessively and had an apparent short radius of curvature, a deep anterior chamber, miotic and dyscoric pupil, and iris hypoplasia. Pupillary light responses were decreased or absent and pupils failed to dilate after repeated instillation of mydriatic drugs in horses with multiple ocular anomalies. Less frequently encountered abnormalities included peripheral iridocorneal adhesions and goniosynechiae. Congenital cataract was always present in eyes with multiple abnormalities. Intraocular pressures did not differ among horses with normal eyes and horses with multiple ocular abnormalities. Histologic examination of eyes corroborated the clinical appearance.

Mechanism of compound- and species-specific food effects of structurally related antiarrhythmic drugs, disopyramide and bidisomide.

PURPOSE: To determine mechanism of food effects observed with bidisomide but not with the structurally similar drug, disopyramide. METHODS: Food effect studies of bidisomide and disopyramide were conducted with and without a standardized high fat meal in healthy subjects and in the dog. Intestinal metabolism of disopyramide and absorption of the metabolites were examined after oral administration of the drug to the dogs with portal vein canula implanted. Effects of food or a mixture of amino acids on metabolism of [14C]disopyramide were examined after intraportal infusion of the drug with and without high fat meal and after drug infusion into portal vein with the amino acid mixture, respectively. RESULTS: The systemic availability of bidisomide was markedly reduced with food in humans, whereas the systemic availability of disopyramide did not change notably. In the dog, the systemic availability of bidisomide was also reduced with food. The systemic availability of disopyramide did not change with food. This was due to the fact that reduction in absorption was compensated by reduction of metabolism. There was no evidence for reduction in hepatic and intestinal metabolism with food. CONCLUSIONS: The apparent reduction in disopyramide metabolism with food may be due to an increase in colonal and/or lymphatic absorption. Food effects on the apparent systemic availability of bidisomide and disopyramide in the dog were similar to those in the rat. However, there was substantial species difference in the mechanism of food effects.

Carbon and oxygen isotope ratios of ecosystem respiration along an Oregon conifer transect: preliminary observations based on small-flask sampling.

Isotope ratio analyses of atmospheric CO(2) at natural abundance have significant potential for contributing to our understanding of photosynthetic and respiration processes in forest ecosystems. Recent advances in isotope ratio mass spectrometry allow for rapid, on-line analysis of small volumes of CO(2) in air, and open new research opportunities at the ecophysiological, whole-organism, and atmospheric levels. Among the immediate applications are the carbon and oxygen isotope ratio analyses of carbon dioxide in atmospheric air. Routine analysis of carbon dioxide in air volumes of approximately 50-300 &mgr;l is accomplished by linking a commercially available, trace gas condenser and gas chromatograph to an isotope ratio mass spectrometer operated in continuous-flow mode. Samples collected in the field are stored in either gas-tight syringes or 100-ml flasks. The small sample volume required makes it possible to subsample the air in flasks for CO(2) and then to sample the remaining air volume for the analysis of the isotopic composition of either methane or nitrous oxide. Reliable delta(13)C and delta(18)O values can be obtained from samples collected and stored for 1-3 days. Longer-term storage, on the order of weeks, is possible for delta(13)C measurements without drift in the isotope ratio signal, and should also be possible for delta(18)O measurements. When linked with an infrared gas analyzer, pump and flask sampling system, it is feasible to sample CO(2) extensively in remote forest locations. The air-sampling system was used to measure the isotope ratios of atmospheric CO(2) and to conduct a regression analysis of the relationship between these two parameters. From the regression, we calculated the delta(13)C of ecosystem respiration of four coniferous ecosystems along a precipitation gradient in central Oregon. The ecosystems along the coast-to-interior Oregon (OTTER) gradient are dominated by spruce-hemlock forests at the wet, coastal sites (> 200 cm precipitation annually) to juniper woodlands (20 cm precipitation) at the interior, dry end of the transect. The delta(13)C values of ecosystem respiration along this transect differed by only 1.3 per thousand (range of -25.2 to -23.9 per thousand ) during August at the peak of the summer drought. Following autumn rains in September, the delta(13)C of ecosystem respiration in the four stands decreased; overall the difference in the carbon isotope ratio of ecosystem respiration among sites increased to 3.9 per thousand (-26.8 to -22.9 per thousand ).

Surgery for glaucoma.

Most cases of glaucoma in small animals ultimately require surgical treatment for long-term control of intraocular pressure. Surgical procedures that have the potential to preserve vision in acute cases are categorized into those that reduce aqueous production (cyclodestructive techniques). Salvage procedures for irreversibly blind eyes include enucleation, implantation of an intraocular prosthesis, and pharmacologic ciliary body ablation. The indications, surgical technique, and complications of these procedures are discussed in this article.

Mechanisms of food effects of structurally related antiarrhythmic drugs, disopyramide and bidisomide in the rat.

PURPOSE: To determine whether the rat is a good animal model for the food effects observed with bidisomide but not with the structurally similar antiarrhythmic drug, disopyramide in man and to explore a reason for the differences in the food effects of these compounds. METHODS: The following effects on the absorption of bidisomide and/or disopyramide were examined in the rat: Food effects, gastrointestinal transit time under fasting and nonfasting conditions, pH effects, hypertonic solution effect of NaCl and glucose, bile effects, permeability, inhibitory effects by Gly, Gly-Gly, Gly-Pro, glucose and mannitol and drug binding to food. RESULTS: Remarkable food effects were observed with bidisomide but not with disopyramide. There was no difference in the GI transit time with and without food. The pH effect with and without food was similar. Effect of salt concentrations on bidisomide and disopyramide was similar. There was no bile effect on absorption of both compounds. Binding of bidisomide and disopyramide to food was similarly low. The apparent permeability of bidisomide was much lower than disopyramide especially in the ileum and its absorption was more inhibited by Gly, Gly-Gly and Gly-Pro. CONCLUSIONS: In the rat, as previously seen in humans, the food effect was observed with bidisomide but not with disopyramide. This difference was in part due to both lower intestinal permeability of bidisomide compared to disopyramide and greater inhibition of absorption by the amino acid, Gly and the dipeptides, Gly-Gly and Gly-Pro.

Effects of SC-52458, an angiotensin AT1 receptor antagonist, in the dog.

We have previously reported on the basic pharmacologic properties of SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), a novel angiotensin (AII) receptor antagonist that binds potently to AT1 receptors in rat adrenal cortex and blocks AII-mediated contraction in isolated rabbit aorta. In the present study, the ability of SC-52458 to block AII pressor responses in conscious dogs was measured. In addition, we determined whether SC-52458 lowered mean arterial pressure in dogs with 2 kidney/1 clip renal hypertension when given daily for 4 days. In conscious, normotensive dogs, SC-52458 at 30 mg/kg orally, blocked the pressor response to AII (50 ng/kg, intravenously) with maximal inhibition (91%) observed 2 h after dosing. Plasma concentrations of SC-52458 measured by HPLC also were highest at the 2-h time point. After 24 h, the AII pressor response remained inhibited (by 35%) and SC-52458 was still measurable in plasma from treated dogs. In dogs made hypertensive by constriction of the left renal artery, SC-52458 lowered mean arterial pressure compared to vehicle treatment although heart rate was not different in the two groups. The maximal blood pressure lowering achieved with SC-52458 was similar to the maximal effect observed with the angiotensin converting enzyme inhibitor lisinopril. We conclude that SC-52458 blocks AII mediated pressor responses in normotensive, conscious dogs and SC-52458 is an efficacious antihypertensive agent in dogs with 2 kidney/1 clip renal hypertension.

Characteristics of participants in domestic violence. Assessment at the scene of domestic assault.

OBJECTIVE: To evaluate the characteristics of victims and perpetrators of domestic assault. DESIGN AND SETTING: Consecutive-sample survey study conducted at the scenes of police calls for domestic assault in Memphis, Tenn, in 1995. PARTICIPANTS: A total of 136 participants (72 victims and 64 assailants) involved in 62 incidents of domestic violence and 75 adult family members at the scene. MAIN OUTCOME MEASURES: Participants' responses to a confidential survey and review of police records. RESULTS: Of 62 episodes of domestic assault, 42 (68%) involved weapons and 11 (15%) resulted in serious injury. Fifty-five (89%) of 62 assault victims reported previous assaults by their current assailants, 19 (35%) of them on a daily basis. Although nearly all assault victims had called the police for help on previous occasions, only 12 (22%) reported having ever sought medical care, counseling, or shelter because of domestic assault. Sixty (92%) of the 64 assailants reportedly used alcohol or other drugs on the day of the assault. Of the assailants, 28 (44%) had a history of arrest for charges related to violence, and 46 (72%) had an arrest for substance abuse. Eleven (15%) of the victims were children. Children directly witnessed 53 (85%) of the assaults. CONCLUSIONS: Most victims of domestic violence who had called the police rarely used medical or mental health facilities for problems related to family violence despite frequent assaults. Victims and assailants were willing to discuss their histories of family violence and undergo assessments at the scenes of police calls.

Force responses to constant-velocity shortening of electrically stimulated human muscle-tendon complex.

Force-velocity curves in human muscle often have unexpectedly high forces at high velocities. If series elasticity is the cause, it should have less effect at lower activation levels and larger shortening amplitudes. The first dorsal interosseus muscle-tendon complex was shortened at different levels of activation and by different amplitudes. Force-velocity curves had high force well maintained at high velocities. With an actuator release of 4.21 mm at 80% of maximal activation, force was > 45% of isometric force (Po) for all actuator velocities > 200 mm/s (1.49 muscle lengths/s). At 30% activation, the force was > 25% of Po at these velocities. The smaller 2.46-mm releases produced higher forces than the 4.21-mm releases at these velocities. At 80% activation, force was > 65% of Po, and at 30% activation, it was > 50% of Po at these velocities. Corrections of these data for elasticity produced classic Hill-type force-velocity curves. A model incorporating the Hill force-velocity equation and a spring in series accounts for the results.

Measurement of muscle and tendon stiffness in man.

Human first dorsal interosseous muscle was stimulated tetanically using several levels of percutaneous electrical current which produced forces in the muscle-tendon complex of between 30% and 100% of maximum. During the tetanus the muscle was subjected to a small fast stretch. The ratio of the force response to the displacement of the muscle-tendon complex gave a measure of the stiffness of the total complex. An adaptation of the method of Morgan (1977) allowed the stiffness to be separated into two components the stiffness of the muscle fibres and the stiffness of the tendon. The results showed that at full activation the stiffness of the muscle fibres and the tendon are approximately the same. The normalised stiffness values obtained in the experiments compared well with animal data.

Metabolism of a novel antiarrhythmic agent, bidisomide, in man: use of high resolution mass spectrometry to distinguish desisopropyl bidisomide from desacetyl bidisomide.

1. Metabolism of bidisomide, a novel antiarrhythmic agent, was studied in man, and was not extensive as evidenced by the fact that approximately 60 and 70% of the radioactive doses were recovered as the parent drug after i.v. and oral administration respectively. 2. The mass spectra of bidisomide metabolites indicate that the two major metabolic pathways of bidisomide were hydroxylation of the piperidine ring and N-dealkylation. The latter occurred on the side chain containing the piperidine ring or the isopropyl group. The N-dealkylated metabolite on the side chain containing the piperidine ring was cyclized to result in a pyrrolidone metabolite. 3. The N-dealkylated metabolite, desisopropyl bidisomide, was identified by comparing its high resolution mass spectrum to that of authentic desacetyl bidisomide. 4. In the hydroxylation pathway, both mono- and dihydroxylated metabolites of the piperidine ring were observed. The exact location of the hydroxyl groups on the piperidine ring was not determined.

Species dependent esterase activities for hydrolysis of an anti-HIV prodrug glycovir and bioavailability of active SC-48334.

PURPOSE: The in vitro fate of an ester prodrug, glycovir, was studied to determine if the species differences in the bioavailability of pharmacologically active SC-48334 observed after glycovir administration and not observed after SC-48334 administration is due to species differences in ester hydrolysis rate or species differences in absorption of the prodrug itself, and to determine the site(s) of ester hydrolysis which contributes most to species differences in the bioavailability of SC-48334 if any. METHODS: Glycovir was incubated with small intestinal mucosa, liver S9 fractions, whole blood, red blood cells (RBC) and plasma of the rat, dog, monkey (cynomolgus and rhesus) and man, and glycovir concentrations were determined by HPLC. RESULTS: The relative bioavailabilities of SC-48334 after prodrug administration to the rat, dog, monkey and man were 99, 15, 42 and 37%, respectively. After SC-48334 administration, SC-48334 was rapidly and similarly well absorbed in all species. The hydrolysis rate in the small intestinal mucosa was well correlated with the relative bioavailability of SC-48334 after prodrug administration. Among different species the hydrolysis rate of glycovir in liver S9 fractions, blood, RBC and plasma did not parallel those in the mucosa of the small intestine. CONCLUSIONS: The species differences in bioavailability of SC-48334 with the prodrug were due to species differences in hydrolysis rates of the prodrug in small intestinal mucosa. The monkey was a good animal model for prediction of esterase activity in human small intestine and relative bioavailability in man.

Effects of SC-56525, a potent, orally active renin inhibitor, in salt-depleted and renal hypertensive dogs.

SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1 +/- 16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.