Mono- and bis(aminomethyl)phenylacetic acid esters as short-acting antiarrhythmic agents. 2.

The synthesis, antiarrhythmic activity, and blood hydrolysis properties of a series of mono- and bis(aminomethyl)phenylacetic acid esters related to a previously reported class Ic antiarrhythmic agent (ACC-9358) are described. Of the various oxa-, aza-, thia-, and carbacyclic esters initially prepared in the bis(pyrrolidinomethyl)-4-hydroxyphenylacetic acid series, the 1,4-benzodioxanyl-2-methyl(3q) and the thienyl-2-methyl(31) esters were evaluated in vivo for antiarrhythmic efficacy. In addition, a number of monoappended phenylacetic esters of 3q with or without the 4-hydroxy group were also prepared for evaluation of antiarrhythmic, lipophilic, and metabolic properties. Of these compounds, 3q possessed the most desirable pharmacological and pharmacokinetic profile.

Ester derivatives of 2,6-bis(1-pyrrolidinylmethyl)-4-benzamidophenol as short-acting antiarrhythmic agents. 1.

In an effort to find a replacement for the iv antiarrhythmic drug lidocaine having reduced systemic and central nervous system effects, activity against supraventricular as well as ventricular arrhythmias, and a biological half-life of less than 15 min, derivatives of the orally active class Ic clinical agent 2,6-bis(1-pyrrolidinylmethyl)-4-benzamidophenol, 1 (ACC-9358), were synthesized and tested. Compounds with ester groups attached to the phenyl ring were either weakly active or toxic. Replacement of the formanilide function with alkyl esters afforded compounds with antiarrhythmic activity in the range of 1. When the ester carboxyl was separated from the bis(aminomethyl)phenol by methylene units, very short half-lives were observed in human blood. In general, these compounds also had low lipophilic character.

PT-141: a melanocortin agonist for the treatment of sexual dysfunction.

PT-141, a synthetic peptide analogue of alpha-MSH, is an agonist at melanocortin receptors including the MC3R and MC4R, which are expressed primarily in the central nervous system. Administration of PT-141 to rats and nonhuman primates results in penile erections. Systemic administration of PT-141 to rats activates neurons in the hypothalamus as shown by an increase in c-Fos immunoreactivity. Neurons in the same region of the central nervous system take up pseudorabies virus injected into the corpus cavernosum of the rat penis. Administration of PT-141 to normal men and to patients with erectile dysfunction resulted in a rapid dose-dependent increase in erectile activity. The results suggest that PT-141 holds promise as a new treatment for sexual dysfunction.

Pharmacology and pharmacokinetics of esmolol.

Esmolol is an ultra-short-acting beta-adrenergic blocking agent that possesses minimal partial agonist activity or direct membrane depressant activity. The short duration of action of esmolol is attributable to rapid enzymatic hydrolysis by red blood cell esterases, forming ASL-8123 and methanol. Experiments in the constant-flow-perfused isolated canine hindlimb indicate that therapeutic (beta blocking) doses of esmolol lack direct vascular effects and alpha-adrenergic blocking activity and that therapeutic doses do not interfere with vascoconstrictor effects of peripheral sympathetic nerve stimulation. Esmolol produces cardiac electrophysiologic and hemodynamic effects consistent with those of beta blockade. Specifically, esmolol decreases heart rate, depresses atrioventricular nodal conduction, and decreases determinants of myocardial oxygen demand. The beneficial antiarrhythmic and infarct-size limiting effects of esmolol have been demonstrated in several experimental models. Whereas beta blockers in general are effective in settings of supraventricular arrhythmias, sinus tachycardia, and myocardial ischemia, esmolol provides the added dimension of "titratability." Thus, the short duration of action of esmolol allows for very rapid titration to a preferred steady-state level of beta blockade; rapid adjustment to different steady-state levels of beta blockade, as may be required by changing status of the patient, and rapid disappearance of beta blockade following discontinuation of esmolol infusion, should this be necessary in the event of deleterious cardiac hemodynamic effects. Thus, esmolol is ideally suited for use in the treatment of patients in whom beta blockade is desirable, but in whom level of beta blockade must be very carefully modulated.

Safety, tolerance and pharmacokinetics of intravenous doses of the phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin: a new prodrug of phenytoin.

A new prodrug of phenytoin, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin (ACC-9653), was administered intravenously over 30 minutes to four different groups of volunteers at doses of 150, 300, 600, and 1200 mg. The prodrug and phenytoin were measured in plasma samples, collected at specified times, by specific high performance liquid chromatography (HPLC) assays. The prodrug, after achieving a maximum concentration at the end of the 30-minute infusion (Cmax 20, 36, 75, 129 micrograms/mL) declined rapidly with a half-life (t1/2) of about 8 minutes. The area under the plasma concentration-time curve (10, 19, 43, 77 mg.hr/L) was proportional to dose whereas the total clearance, 14 L/hr, was independent of dose. The volume of distribution of the prodrug, a polar, water-soluble molecule was about 2.6 L, indicating that most of the dose remained in the plasma. The concentration of phenytoin reached 90% of its maximum about 12 minutes after the end of the infusion of ACC-9653. At the dose of 1200 mg of prodrug, the average peak concentration of phenytoin was about 17 micrograms/mL, near the upper limit of the therapeutic range. Adverse reactions (lightheadedness, nystagmus, incoordination) were minor and attributed to phenytoin. No significant abnormalities in ECG, Holter monitoring, or EEG were noted after the infusion of ACC-9653.

Protein binding of brequinar in the plasma of healthy donors and cancer patients and analysis of the relationship between protein binding and pharmacokinetics in cancer patients.

The protein binding of weakly acidic and basic drugs has been shown to be altered in cancer patients. Brequinar is a weakly acidic, low-clearance, and highly protein-bound (> 98% bound) antitumor agent. The pharmacokinetic parameters of brequinar are subject to large interpatient variability. This large interpatient variability may be related to brequinar's plasma protein-binding capacity (assuming no change in the intrinsic clearance of the unbound drug). The objectives of this study, therefore, were (a) to characterize brequinar's protein binding in the plasma of healthy donors and cancer patients and (b) to examine the relationships between brequinar's plasma protein binding and its pharmacokinetics in patients. Brequinar protein binding was determined in human serum albumin (HSA) solution, drug-free donor plasma, and brequinar-free, predose plasma samples obtained from a phase I cancer trial. Pharmacokinetic results from this study were used to examine relationships between plasma protein binding and drug disposition. In HSA solution and healthy donor plasma, brequinar's protein binding as determined using spiked samples was concentration-dependent. The unbound brequinar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4% HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor plasma as the brequinar concentrations increased from 0.1 to 2.3 mM in the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysis of brequinar binding characteristics using the binding ratio and Rosenthal binding plots showed that albumin was the primary protein for brequinar binding in human plasma. The addition of various concentrations of alpha 1-acid glycoprotein to 4% HSA solution did not affect the protein binding of brequinar to HSA. The protein binding determined in the plasma of cancer patients was not quantitatively different, except for variability, from that observed in the plasma of healthy donors. Examination of relationships between the unbound brequinar fraction and pharmacokinetics suggested that plasma protein binding was not a major determinant of brequinar disposition in cancer patients.

Biological matrix-dependent pharmacokinetic and pharmacodynamic parameters of a novel platelet glycoprotein IIB/IIIA receptor antagonist, XU063, in beagle dogs.

The pharmacokinetic-pharmacodynamic (PK/PD) relationship of a novel platelet glycoprotein IIb/IIIa receptor antagonist, XU063, was evaluated as a function of biological matrix in beagle dogs. The disposition of 14C-radioactivity in various blood or plasma matrices and kinetics of inhibition of adenosine diphosphate (ADP) induced platelet aggregation were determined in beagle dogs following an intravenous infusion of 14C-XU063 at 2 micrograms/kg for 45 min. The 14C-radioactivity was maximum in platelet poor plasma (PPP) harvested from blood collected in EDTA and lowest in PPP harvested from blood collected in citrated vacutainers over the entire concentration versus time profile during and post infusion. The 14C-radioactivity values in blood and platelet rich plasma (PRP) were comparable and were between EDTA PPP and citrated PPP values. The resultant estimates of the PK and PD parameters of 14C-XU063 varied widely depending on the type of matrix used. The systemic clearance values for 14C-XU063 were 1 and 10 mL/min/kg for EDTA and citrated PPP, respectively. The values for the volume of distribution at steady-state were 0.2 and 1.3 L/kg, for EDTA and citrated PPP, respectively. The terminal elimination half-life appeared independent of the matrix with a median value of 2 h. The estimated ex vivo IC50 values of XU063 ranged from 0.4 ng/mL (citrated PPP, platelet free drug) to 7 ng/mL (EDTA PPP, total drug). These results demonstrated the dependence of PK and PD parameters of antiplatelet agent XU063 on the type of biological matrix used to determine concentrations of XU063. The pros and cons of various blood sample collection methods for the evaluation of PK/PD relationship of potential antiplatelet agents are presented.

Determination of DuP 128, an ACAT inhibitor and its sulphoxide and sulphone metabolites in human plasma by liquid chromatography.

A sensitive and specific high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed for the simultaneous determination of DuP 128 (N'-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)p entyl]-N- hepthylurea), an ACAT inhibitor, its sulphone metabolite (XB277), and the separate determination of sulphoxide metabolite (XC164) in human plasma. After deproteinizing plasma samples with acetonitrile, the organic layer, created by adding approximately 0.25 g of NaCl, was removed, evaporated to dryness, and the residue then reconstituted with 400 microliters of acetonitrile. The acetonitrile layer was washed with 5 ml of hexane and then 50 microliters was injected into the HPLC. DuP 128 and XB277 were simultaneously quantified using a YMC basic column and fluorescence detection (lambda Ex = 270 nm and lambda Em = 385 nm). XC164 was quantified using a Waters microBondpack C18 reversed-phase column and fluorescence detection (lambda Ex = 270 nm and lambda Em = 365 nm). The relationship between the peak height and plasma concentrations best fit a power curve and showed an average correlation coefficient of > 0.99 over a concentration range of 1-200 ng ml-1 for DuP 128 and XC164 and 2.5-200 ng ml-1 for XB277. Good intraday and interday assay precisions (RSD < 10%) and accuracy (< 14%) for all three compounds were observed. The methods were sufficiently sensitive and selective to quantify plasma concentrations of DuP 128 and its sulphoxide and sulphone metabolites after oral administration of single or multiple dose(s) of > 350 mg of DuP 128 to healthy subjects.

Pharmacodynamics and onset of action of esmolol in anesthetized dogs.

The pharmacodynamics and onset of action of esmolol, a novel, cardioselective beta adrenergic receptor antagonist with an ultra short duration of action, were studied in anesthetized dogs. Steady-state levels of beta blockade were attained within 10 min after initiation of esmolol infusion or when changing infusion rates. Similarly, steady-state blood levels of esmolol were attained within 30 min (the earliest sampling point) after starting an infusion and new steady-state blood levels were re-established again within 30 min after changing the infusion rates. Rapid recovery from beta blockade after termination of the esmolol infusion was paralleled by a rapid decline in blood levels of esmolol. The duration of action and elimination half-life both averaged less than 15 min. Excellent linear correlations were obtained between dose and steady-state blood concentration and the logarithm of the steady-state blood concentration and percentage of beta blockade. In a separate study, the onset of beta blockade with esmolol was observed within 15 sec of initiating a 60-sec infusion of 500 micrograms/kg/min. Peak beta blockade occurred at 30 to 45 sec after switching to a maintenance dose of 12.5, 25 or 50 micrograms/kg/min. The duration of peak effect was dependent on the maintenance dose. Peak blood levels of esmolol occurred immediately after stopping the loading dose and decreased to steady-state blood levels at 20 and 10 min after maintenance doses of 25 and 50 micrograms/kg/min, respectively. The results of these studies indicate that the onset, time to steady state and termination of beta blockade with esmolol are rapid and that an excellent correlation exists between the blood level of the drug and degree of beta blockade both during and after an esmolol infusion.

Biochemical characterization of flestolol esterase.

The blood esterase that mediates the metabolism of flestolol, an ultra short-acting beta blocker, was characterized. Esterase activity occurred in plasma of human, dog, rat, and guinea pig and not in erythrocytes of the same species. The esterase activity was greatest in humans and guinea pigs followed by dogs and rats. Purified human serum cholinesterase was very active against flestolol while human serum albumin was slightly active. Human and bovine erythrocyte membrane acetylcholinesterases, electric eel acetylcholinesterase, human hemoglobin, dog, rat, chicken, and bovine serum albumin were all inactive. Esterase activity with flestolol was inhibited in human, dog, and rat blood by echothiophate, eserine, and sodium fluoride. Guinea pig blood esterase activity was inhibited by echothiophate and sodium fluoride, but not by eserine. Metabolic interaction studies indicated that succinylcholine, procaine, and chloroprocaine interfere with the metabolism of flestolol in human blood. Succinylcholine prolonged the in vitro half-life of flestolol in dog blood, but acetylcholine, procaine, and chloroprocaine had no effect. Flestolol did not affect the metabolism of procaine or chloroprocaine in human and dog blood. The metabolism rate of flestolol decreased in individuals with atypical, fluoride-resistant and silent forms of serum cholinesterase.

Polymorphic metabolism of flestolol and other ester containing compounds by a carboxylesterase in New Zealand white rabbit blood and cornea.

Flestolol, N(1,1-dimethyl-2-ureidocthyl)-2-hydroxy-3-(o-fluorobenzoyloxy++ +) propylamine, (F), is an ester containing an ultra short-acting beta blocker intended for the treatment of myocardial dysfunctions. In vitro incubation of F, procaine, chloroprocaine, and atropine with blood from different New Zealand White (NZW) rabbits resulted in a bimodal distribution (70% fast, 30% slow) of ester hydrolysis rates. Using F as a model substrate, bimodal hydrolysis rates were also observed in NZW rabbit cornea but not aqueous humor, iris-ciliary body complex and ocular tissues of pigmented rabbits. In addition, the bimodal distribution of esterase activity was not observed in blood from rats, dogs, and humans. Incubation of esters at various positions of the phenoxypropanolamine nucleus of beta blockers with NZW rabbit blood indicated structural specificity of the carboxylesterase in terms of unimodal or biomodal distribution of activity. These results strongly suggest that the carboxylesterase in NZW rabbit blood that hydrolyzes F and similar compounds is atropine esterase as described in the literature.

Biochemical properties of blood esmolol esterase.

The blood esterase mediating the hydrolysis of esmolol was characterized in several different species including man. In contrast to most ester-containing drugs, hydrolysis of esmolol was mediated by an esterase in the cytosol of red blood cells (RBC) in man and dogs and not in plasma or RBC membrane. Species differences in the esterase activity existed. Guinea pig and rat blood esterase activities were much greater than those in the dog followed by those in man. In addition, the esterase activity in rat and guinea pig blood was localized in plasma and not in RBC. Purified human serum cholinesterase, human RBC membrane acetylcholinesterase, human hemoglobin, human carbonic anhydrases A and B, and human and dog serum albumin were all inactive against esmolol. Esmolol esterase activity in human and dog blood was inhibited by sodium fluoride, EDTA, and p-hydroxymercuribenzoate, but not by echothiophate, eserine, and acetazolamide. In contrast, echothiophate and sodium fluoride, but not eserine, inhibited the esterase activity in rat and guinea pig plasma. Metabolic interaction studies indicated that acetylcholine, succinylcholine, procaine, and chloroprocaine did not interfere with the metabolism of esmolol by human and dog blood. Based on the results, it appeared that an arylesterase in human and dog RBC cytosol mediated the hydrolysis of esmolol while an aliphatic esterase mediated the hydrolysis of esmolol in guinea pig and rat plasma.

Beta-adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol.

The beta-adrenoreceptor antagonist properties of ASL-8123, the primary metabolite of esmolol, were determined in vitro and in vivo. ASL-8123 demonstrated weak competitive beta-adrenoreceptor blocking activity in isolated guinea pig right atria with a pA2 of 3.73 +/- 0.07; no agonist-like activity was observed in this tissue at concentrations of ASL-8123 from 3 X 10(-5) to 1 X 10(-2) M. In anesthetized dogs, ASL-8123 was infused at increasing dosages from 0.2-25.6 mg/kg/min, each dose rate maintained for 20 min. The compound produced a slight decrease in heart rate of 15-22 beats/min at cumulative doses of 508-1,020 mg/kg and decreased diastolic blood pressure by 14-47 mm Hg at cumulative doses of 252-1,020 mg/kg. ASL-8123 dose-dependently inhibited the heart rate and diastolic blood pressure responses to isoproterenol (0.5 micrograms/kg i.v.). Blood levels of ASL-8123 were linearly correlated with inhibition of the heart rate response to isoproterenol (r = 0.95-0.99 for each dog, n = 6). The blood level of ASL-8123 that produced a 50% inhibition of isoproterenol-induced tachycardia averaged 293 +/- 65 micrograms/ml. Recovery from beta-adrenoreceptor blockade after terminating the infusion of ASL-8123 occurred slowly, decreasing from 81% at the end of the infusion to 55% 60 min later, and was paralleled by a slow decrease in blood levels of ASL-8123. Thus, ASL-8123 is a weak beta-adrenoreceptor antagonist which is approximately 1,600-1,900 times less potent than its parent, esmolol.

Binding of fosphenytoin, phosphate ester pro drug of phenytoin, to human serum proteins and competitive binding with carbamazepine, diazepam, phenobarbital, phenylbutazone, phenytoin, valproic acid or warfarin.

The protein binding of [14C]fosphenytoin, (3-phosphoryloxy-methyl phenytoin disodium), a phosphate ester prodrug of phenytoin sodium, to human serum proteins, serum albumin and alpha 1-acid glycoprotein was determined by ultrafiltration. The mean +/- SD% of fosphenytoin bound to human serum proteins was 95.7 +/- 0.48%. Binding to albumin (36.5 mg/ml) decreased linearly from 89.2 to 67.3% when the fosphenytoin concentration was increased from 6 to 200 micrograms/ml. Fosphenytoin was weakly bound to alpha 1-acid glycoprotein (13.3%). Simultaneous incubation with high concentrations of carbamazepine (10 micrograms/ml) and diazepam (5 micrograms/ml) or therapeutic concentrations of phenytoin (10 micrograms/ml) had no effect on the binding of fosphenytoin to human serum proteins. High concentrations of phenobarbital (160 micrograms/ml), phenytoin (50 micrograms/ml), or valproic acid (500 micrograms/ml), however, caused slight, but significant, increases in the free fraction of fosphenytoin in serum protein. Phenylbutazone and sulfisoxazole resulted in a 48% increase in fosphenytoin free fraction while warfarin had a slight (8%), but significant, increase in free fraction of fosphenytoin. It was concluded that the concentration of albumin was the most important determinant for the plasma free fraction of fosphenytoin in man. Potential increase in fosphenytoin clearance may be observed in hypoalbuminemia.

Species differences in the stereoselective hydrolysis of esmolol by blood esterases.

The stereoselective hydrolysis of esmolol was examined in blood from several species including humans. Blood esmolol esterase activity was in the order of guinea pigs greater than rats greater than rabbits greater than dogs greater than rhesus monkeys greater than humans. Dog and rat blood esterases hydrolyzed the (-)-enantiomer of esmolol faster than the (+)-enantiomer whereas rhesus monkey, rabbit, and guinea pig blood esterases hydrolyzed the (+)-enantiomer faster. Human blood esterases did not demonstrate stereoselectivity. Dog liver esterases also showed stereoselectivity towards the (-)-enantiomer but dog skeletal muscle esterases did not. Studies in mongrel dogs indicated that during esmolol infusions the concentration ratio of (-)-esmolol/(+)-esmolol was approximately 0.85. After termination of the esmolol infusion the (-)/(+) concentration ratio continuously decreased until (-)-esmolol was no longer quantifiable. These results indicate that stereoselective hydrolysis of esmolol occurs in vitro and in vivo.

Metabolism and disposition of EXP631--a novel antidepressant analgesic.

EXP631, 4-(3-thienyl)-alpha, alpha,1-trimethyl-4-piperidine-methanol hemi-fumarate salt (I), is a centrally acting non-opioid analgesic compound with monoamine uptake blocking properties. EXP631 has analgesic effects in several animal models. It is intended to be used for the treatment of moderate to moderately severe acute and chronic pain. To characterize the disposition of EXP631, the plasma levels of EXP631 were determined in rats and dogs after single intravenous and oral doses. In rats, EXP631 was rapidly absorbed following a single oral solution dose of 5-20 mg kg-1 with maximum plasma levels detected within 1.2 h post dose. The absorption was complete with an oral bioavailability of 92-131%. The pharmacokinetics was dose independent as measured by either Cmax or AUC values. In fasted dogs, EXP631 was absorbed rapidly and well (F = 81%) from an oral solution with the maximum concentration detected at 20 min post dose. In fed dogs, the absorption from capsules was slower (1.38 h) compared to the solution, but the absorption was complete (F = 115%). An N-desmethyl metabolite (II) was found in both rat and dog plasma samples. The structure was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy and comparative chromatographic retention times. The metabolite is inactive as an analgesic.

Influence of temperature on in vitro metabolism of esmolol.

Esmolol has been used to improve hemodynamic stability during sternotomy and aortic manipulation for coronary artery bypass graft surgery. In order to investigate the alterations of esmolol metabolism by hypothermic cardiopulmonary bypass (CPB), the effect of temperature on the metabolism of esmolol in vitro was determined. Samples of human whole blood were combined with esmolol solution (50 micrograms/mL in 0.9 mol/L NaCl) and incubated at 4 degrees C, 15 degrees C, 25 degrees C, and 37 degrees C. Aliquots were sampled at 1, 5, 10, 15, 30, 60, and 120 minutes; esmolol concentration was determined using high-pressure liquid chromatography. There was a temperature-dependent decrease in the degradation of esmolol. The half-life for esmolol in human blood was 19.6 +/- 3.8 minutes at 37 degrees C, 47 +/- 10.1 minutes at 25 degrees C, 152 +/- 46.6 minutes at 15 degrees C, and 226.7 +/- 60.1 minutes at 4 degrees C. This study clearly shows marked reduction of esmolol metabolism with hypothermia possibly leading to persistent beta-adrenergic blockade following the discontinuation of CPB. Persistent beta-blockade may provide additional protection to the ischemic myocardium during hypothermic arrest and/or result in difficulty in weaning from CPB.

The effect of hepatic disease on the disposition of moricizine in humans.

The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased Cmax (59%), an increased t1/2 (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for tmax and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.

Pharmacokinetics of HIV protease inhibitor DMP 323 in rats and dogs.

DMP 323 is a symmetrically substituted cyclic urea compound with demonstrated activity against human immunodeficiency virus (HIV) in vitro. DMP 323 has been measured in rat and dog plasma via liquid-liquid extraction and HPLC. The limit of quantitation is 10 ng/ml using 0.5 ml plasma. Following an intravenous dose of 5 mg/kg to rats, DMP 323 exhibited an apparent volume of distribution at steady-state of 6.36 liters/kg and clearance of 7.12 liters/hr/kg. The same dose administered intravenously to dogs resulted in apparent volume of distribution at steady-state and clearance values of 2.28 liters/kg and 1.48 liters/hr/kg, respectively. Elimination half-lives were 0.95 hr in rats and 1.80 hr in dogs. DMP 323 was rapidly absorbed from oral solution doses in rats (3, 5, and 10 mg/kg) and dogs (5 and 10 mg/kg), achieving maximum plasma concentrations in 1 hr or less in both species. Absolute bioavailability of DMP 323 from oral doses ranged from 15 to 27% in rats and from 37 to 38% in dogs. Pharmacokinetics were unchanged in rats and dogs over 8-day t.i.d. and 5-day b.i.d. multiple oral dose regimens, respectively. Oral doses administered to fed animals resulted in lower plasma concentrations of DMP 323 than the same doses administered to fasted animals. Because of its in vitro high potency and acceptable pharmacokinetics, DMP 323 seems to be a worthy candidate for further study in the effort to develop an inhibitor of HIV protease for use in the therapy of AIDS.