The pharmacokinetics and disposition of MK-0524, a Prostaglandin D2 receptor 1 antagonist,in rats,dogs and monkeys

MK-0524 is a potent, selective and orally active Prostaglandin D₂ receptor 1 (DP₁) antagonist currently under clinical development for the treatment of niacin-induced flushing. Experiments to study the pharmacokinetics, metabolism and excretion of MK-0524 were conducted in rats, dogs and monkeys. MK-0524 displayed linear kinetics and rapid absorption following an oral dose. Following intravenous (i.v.) administration of MK-0524 to rats and dogs (1 and 5?mg/kg), the mean Cl_p was ～2 and ～6?ml/min/kg, the T_1/2 was ～7 and ～13?h and the Vd_ss was ～1 and ～5 L/kg, respectively. In monkeys dosed i.v. at 3?mg/kg, the corresponding values were 8?ml/min/kg, 3?h and 1?L/kg, respectively. Following oral dosing of MK-0524 to rats (5, 25 and 100?mg/kg), dogs (5?mg/kg) and monkeys (3?mg/kg), the absorption was rapid with the mean C_max occurring between 1 and 4?h. Absolute oral bioavailability values in rats, dogs and monkeys were 50, 70 and 8%, respectively. The major circulating metabolite was the acyl glucuronide of MK-0524 (M2), with ratios of glucuronide to the parent aglycone being highest in the monkey followed by dog and rat. In bile duct-cannulated rats and dogs, MK-0524 was eliminated primarily via acyl glucuronidation followed by biliary excretion of the acyl glucuronide, M2, the major drug-related entity in bile.     

The effect of MK-0524, a prostaglandin D2 receptor antagonist, on prostaglandin D2-induced nasal airway obstruction in healthy volunteers

Introduction Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D₂ is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD₂ reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD₂ (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD₂ can be a useful tool for evaluating DP-receptor antagonists. Objective The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD₂ induced nasal congestion in healthy volunteers. Methods To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD₂ were performed to determine the PD₇₅, which is the intranasal dose of PGD₂ that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry. Results Following treatment with MK-0524, the PD₇₅ (mean±SD) was significantly shifted from 15.8 ± 18.3 μg/nostril during the placebo period to more than 512 μg/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen. Conclusion Whether this >45 fold increase in PD₇₅ will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.     

Metabolism of MK-0524, a prostaglandin D2 receptor 1 antagonist, in microsomes and hepatocytes from preclinical species and humans.

(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The major in vitro and in vivo metabolite of MK-0524 is the acyl glucuronic acid conjugate of the parent compound, M2. To compare metabolism of MK-0524 across preclinical species and humans, studies were undertaken to determine the in vitro kinetic parameters (K(m) and V(max)) for the glucuronidation of MK-0524 in Sprague-Dawley rat, beagle dog, cynomolgus monkey, and human liver microsomes, human intestinal microsomes, and in recombinant human UDP glucuronosyltransferases (UGT). A comparison of K(m) values indicated that UGT1A9 has the potential to catalyze the glucuronidation of MK-0524 in the liver, whereas UGT1A3 and UGT2B7 have the potential to catalyze the glucuronidation in the intestine. MK-0524 also was subject to phase I oxidative metabolism; however, the rate was significantly lower than that of glucuronidation. The rate of phase I metabolism was ranked as follows: rat approximately monkey > human intestine > dog > human liver with qualitatively similar metabolite profiles across species. In all the cases, the major metabolites were the monohydroxylated epimers (M1 and M4) and the keto-metabolite, M3. Use of inhibitory monoclonal antibodies and recombinant human cytochromes P450 suggested that CYP3A4 was the major isozyme involved in the oxidative metabolism of MK-0524, with a minor contribution from CYP2C9. The major metabolite in hepatocyte preparations was the acyl glucuronide, M2, with minor amounts of M1, M3, M4, and their corresponding glucuronides. Overall, the in vivo metabolism of MK-0524 is expected to proceed via glucuronidation, with minor contributions from oxidative pathways.     

The pharmacokinetics of indecainide in mice, rats, dogs, and monkeys

The pharmacokinetics of indecainide, a new antiarrhythmic agent, were studied in mice, rats, dogs, and monkeys. The drug was well absorbed in all species tested resulting in peak plasma levels of drug within 2 hr. The plasma half-life of indecainide after acute oral administration was 3-5 hr in rats, dogs, and monkeys but considerably shorter in mice. The plasma half-life of indecainide was dose-dependent in dogs and increased slightly with chronic dosing. Peak plasma levels of drug were also dose-dependent in dogs and monkeys. Fecal elimination was the primary route of excretion of the drug in rats and mice after oral dosing. Fifty per cent of the dose was excreted in the bile of rats which was then subject to enterohepatic circulation. Urinary elimination was the predominant excretory route in the dog. Tissue distribution of radioactivity in rats showed that tissues which first encounter the drug have the highest levels of radioactivity. The highest concentrations were found in the stomach, intestine, liver, and kidney, whereas very low levels were observed in the fat and brain. Except for liver and kidney, only very low levels were present after 24 hr.     

The metabolic disposition of aprepitant, a substance P receptor antagonist, in rats and dogs.

The absorption, metabolism, and excretion of [14C]aprepitant, a potent and selective human substance P receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting, was evaluated in rats and dogs. Aprepitant was metabolized extensively and no parent drug was detected in the urine of either species. The elimination of drug-related radioactivity, after i.v. or p.o. administration of [14C]aprepitant, was mainly via biliary excretion in rats and by way of both biliary and urinary excretion in dogs. Aprepitant was the major component in the plasma at the early time points (up to 8 h), and plasma metabolite profiles of aprepitant were qualitatively similar in rats and dogs. Several oxidative metabolites of aprepitant, derived from N-dealkylation, oxidation, and opening of the morpholine ring, were detected in the plasma. Glucuronidation represented an important pathway in the metabolism and excretion of aprepitant in rats and dogs. An acid-labile glucuronide of [14C]aprepitant accounted for approximately 18% of the oral dose in rat bile. The instability of this glucuronide, coupled with its presence in bile but absence in feces, suggested the potential for enterohepatic circulation of aprepitant via this conjugate. In dogs, the glucuronide of [14C]aprepitant, together with four glucuronides derived from phase I metabolites, were present as major metabolites in the bile, accounting collectively for approximately 14% of the radioactive dose over a 4- to 24-h period after i.v. dosing. Two very polar carboxylic acids, namely, 4-fluoro-alpha-hydroxybenzeneacetic acid and 4-fluoro-alpha-oxobenzeneacetic acid, were the predominant drug-related entities in rat and dog urine.     

Pharmacokinetics and disposition of DY-9760e, a novel calmodulin antagonist, in rats and monkeys

DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate, CAS 162496-41-5) is a novel calmodulin antagonist that is being evaluated for the treatment of ischemia. The objective of this study was to characterize the pharmacokinetics and disposition of DY-9760e in rats and monkeys. After a 6 h continuous infusion at 1 mg/kg/h to male rats, the plasma concentration of unchanged DY-9760, as the anhydrous free base of DY-9760e, declined with a terminal half-life of 3.0 h. In monkeys, the plasma concentration of DY-9760 following a 4 h continuous infusion at 1 mg/kg/h declined with a terminal half-life of 3.8 h. Total clearance was 18.3 ml/min/kg in rats and 16.7 ml/min/kg in monkeys. The pharmacokinetics of DY-9760e was linear within a dose range from 1 mg/kg to 16 mg/kg in monkeys. After intravenous bolus administration of 14C-DY-9760e to rats, the radioactivity was widely distributed throughout the body except for the brain and testis. In the brain, which is the target organ of this compound, the concentrations of unchanged DY-9760 in rats were much lower than the corresponding plasma concentrations. These results indicated that the permeability of DY-9760 into the brain was restricted. In contrast, the brain concentrations of the N-dealkylated metabolite DY-9836 were approximately 2- to 3-fold higher than those observed in the plasma. The administered radioactivity was excreted mostly in the feces (95.2% in rats, 83.6% in monkeys), and the biliary excretion of the radioactivity in bile duct-cannulated rats was 86.2% within 48 h, part of which (11.1%) was re-absorbed. The urinary excretion of unchanged DY-9760 was less than 0.5% in both species. The metabolic profile characterized by thin-layer chromatography demonstrated that most of the radioactivity in the urine and bile referred to many polar metabolites. These results indicate that DY-9760e is eliminated mainly through hepatic metabolic clearance in both rats and monkeys.     

The disposition, metabolism, and pharmacokinetics of a selective metabotropic glutamate receptor agonist in rats and dogs.

Compound LY354740 [(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid], an analog of glutamic acid, is a selective group 2 metabotropic glutamate receptor agonist in clinical development for the treatment of anxiety. Studies have been conducted to characterize the absorption, disposition, metabolism, and excretion of LY354740 in rats and dogs after intravenous bolus or oral administration. Plasma concentrations of LY354740 were measured using a validated gas chromatography/mass spectrometry assay. In rats, LY354740 demonstrated linear pharmacokinetics after oral administration from 30 to 1000 mg/kg. The oral bioavailability of LY354740 was approximately 10% in rats and 45% in dogs. In the dog, food decreased the mean area under the plasma concentration-time curve value by approximately 34%, hence, decreasing the oral bioavailability of the compound. Excretion studies in both rats and dogs indicate that the absorbed drug is primarily eliminated via renal excretion. In addition, tissue distribution in rats showed that the highest levels of radioactivity were in the kidney and gastrointestinal tract, which is consistent with the excretion studies. Metabolism of LY354740 was evaluated in vitro using rat and dog liver microsomes and rat liver slices. In addition, urine and fecal samples from rat and dog excretion studies were profiled using HPLC with radio-detection. These evaluations indicated that neither rats nor dogs metabolized LY354740. In summary, LY354740 is poorly absorbed in rats, moderately absorbed in dogs, and rapidly excreted as unchanged drug in the urine.     

Absorption, metabolism, and excretion of [(14)C]MK-0524, a prostaglandin D(2) receptor antagonist, in humans.

[(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopentaindol-3-yl]acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The metabolism and excretion of [(14)C]MK-0524 in humans were investigated in six healthy human volunteers following a single p.o. dose of 40 mg (202 microCi). [(14)C]MK-0524 was absorbed rapidly, with plasma C(max) achieved 1 to 1.5 h postdose. The major route of excretion of radioactivity was via the feces, with 68% of the administered dose recovered in feces. Urinary excretion averaged 22% of the administered dose, for a total excretion recovery of approximately 90%. The majority of the dose was excreted within 96 h following dosing. Parent compound was the primary radioactive component circulating in plasma, comprising 42 to 72% of the total radioactivity in plasma for up to 12 h. The only other radioactive component detected in plasma was M2, the acyl glucuronic acid conjugate of the parent compound. The major radioactive component in urine was M2, representing 64% of the total radioactivity. Minor metabolites included hydroxylated epimers (M1/M4) and their glucuronic acid conjugates, which occurred in the urine as urea adducts, formed presumably during storage of samples. Fecal radioactivity profiles mainly comprised the parent compound, originating from unabsorbed parent and/or hydrolyzed glucuronic acid conjugate of the parent compound. Therefore, in humans, MK-0524 was eliminated primarily via metabolism to the acyl glucuronic acid conjugate, followed by excretion of the conjugate into bile and eventually into feces.     

The pharmacokinetics and metabolism of DuP 532, a non-peptide angiotensin II receptor antagonist,in rats and dogs

DuP 532, 2-propyl-4-pentafluoroethyl-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl} imidazole-5-carboxylic acid, is an orally active, non-peptide angiotensin II (AII) receptor antagonist. DuP 532 is more potent and longer acting than losartan, another AII receptor antagonist currently undergoing phase III clinical trials. The pharmacokinetics and the effect of the salt form on the bioavailability of DuP 532 were determined in rats and dogs. In rats, the absolute oral bioavailability and half-life averaged 8·0% and 3·5 h, respectively, after the sodium bicarbonate solution and 7·6% and 3·6 h, respectively, after the methyl cellulose suspension. In dogs, the absolute oral bioavailability averaged 13.4% after the sodium bicarbonate solution and 11·9% after hard gelatin capsules containing the neat powder. The data demonstrated that there were no differences in bioavailability between the free acid and the sodium salt of DuP 532 after oral administration to rats and dogs. The in vitro metabolism of ¹⁴C-DuP 532 was evaluated with rat, dog, and human liver microsomes. HPLC analyses with UV and radiochemical flow detection showed that recovery of DuP 532 was greater than 99%, suggesting that there was little if any metabolism by liver microsomal enzymes. Therefore, the low oral bioavailability in rats was probably due to poor absorption of DuP 532 from the GI tract rather than extensive metabolism.     

The pharmacokinetics and metabolism of CP-191,166, an angiotensin II receptor antagonist, in rats and dogs

CP-191,166 is an orally active, non-peptide angiotensin II (AII) receptor antagonist developed for the treatment of hypertension and congestive heart failure (CHF). In this study, the intravenous (iv) and oral (po) single dose pharmacokinetics (PK), oral multiple dose PK and P450-mediated metabolism of CP-191,166 were determined in rats and dogs. CP-191,166 was administered in both single and multiple (22-29 day) doses to Sprague-Dawley rats (3 mg/kg iv and 5, 10, 25 and 200 mg/kg po) and to beagle dogs (5 mg/kg iv and 5, 15 and 50 mg/kg po). Blood samples were collected between 0 and 48 h and plasma CP-191,166 concentrations were determined using high performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The in vitro metabolism of CP-191,166 was also evaluated with rat and dog liver microsomes. The results of these studies suggest that in both species, there may be saturable clearance occurring with higher doses, T(max) was at or near the earliest sample time point for all doses, suggesting that the drug was rapidly absorbed, and CP-191,166 was eliminated with t(1/2) values of 8-9 h. No rat or dog microsomal metabolism was observed, suggesting that metabolites detected in vivo in dogs were non-P450-mediated.     

Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.

Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1--10 mg/kg p.o.) in rats, with bioavailability>60% at all doses. However, bioavailability was only approximately 20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey > rat approximately human > dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development.     

Paraquat disposition in rats, guinea pigs and monkeys

LD50 doses of ¹⁴C-labeled paraquat were administered to rats, guinea pigs and monkeys by gavage, and radioactivity was determined in excreta and tissues. Rat urine was analyzed for paraquat metabolites by thin-layer chromatography. [¹⁴C]Paraquat was absorbed from the gastrointestinal tract and reached highest serum values 0.5–1 hr after administration. Disappearance of [¹⁴C]paraquat from serum was characterized by a rapid initial decline followed by a prolonged slow decline. Tissue paraquat values were higher than serum values in rats and guinea pigs. Relative to other tissues, paraquat accumulated transiently in the lung and reached peak concentration 32 hr after administration. In rats a major portion of administered paraquat was not absorbed from the gastrointestinal tract. At 32 hr after paraquat, 52% of the administered dose remained in the gastrointestinal tract and 17 and 14% of the administered dose was excreted in the feces and urine, respectively. No radioactivity was recovered in expired air or flatus. Excretion of paraquat in urine and feces was prolonged in all species. In monkeys paraquat was measured in urine and feces 21 days after administration. Chromatography of urine from [¹⁴C]paraquat-treated rats revealed no metabolites. The primary pathologic changes induced by paraquat in the lung may be related to the transient uptake of the chemical by that organ.     

Single dose pharmacokinetics, safety and tolerability of MK-0476, a new leukotriene D4-receptor antagonist, in healthy volunteers.

MK-4076 or sodium 1-(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)- ethenyl)phenyl) 3-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl) cycloproprane) acetate is a novel, potent, and specific LTD4-receptor antagonist. The safety, tolerability and plasma drug profiles of single oral doses of MK-0476 (capsules) were evaluated in 18 healthy male volunteers assigned to one of the two parallel 9-subject panels. Under fasting conditions, increasing single doses of 20 to 800 mg were administered in a first part of the study and in a second part, 200 mg MK-0476 was given either as a solution, under fasting conditions, or as capsules, after a standard breakfast. All volunteers completed the study. Side effects, reported by the investigator to be related to study drug, were mild and transient. No laboratory abnormalities were noted. In the evaluated dose range of MK-0476 (20 to 800 mg) the median value of tmax ranged from 2 to 4 h, while the apparent t1/2 value averaged 4 to 5 h. The median tmax value of the 200 mg capsule dose was not significantly different from the median tmax of the 200 mg oral solution dose indicating that neither disintegration nor dissolution is a rate-limiting step for the absorption of MK-0476 from capsules. There was a statistically significant increase in the AUC (geometric mean ratio of fed/fast was 2.52 with 95% confidence interval of 1.25, 5.06) and in Cmax (geometric mean ratio of fed/fast was 1.36 with 95% confidence interval of 0.60, 3.04) when MK-0476 was given together with a breakfast, suggesting an increase in bioavailability.(ABSTRACT TRUNCATED AT 250 WORDS)     

The metabolic disposition of etodolac in rats, dogs, and man

The metabolic disposition of etodolac (etodolic acid) was studied after oral and intravenous administration of the 14C-labeled or unlabeled drug to rats and dogs, and after oral administration of the drug to man. In all species, peak serum drug levels were attained within 2 hr after dosing. In rats and dogs, virtually all of the oral dose was absorbed; etodolac represented 95% of the serum radioactivity in rats and 75% in dogs. Serum levels in all species were generally dose-related. The elimination portion of the serum drug concentration/time curves was characterized by several peaks, which in rats were shown to be due to enterohepatic circulation. Tissue distribution studies in rats showed that radioactivity localized primarily in blood vessels, connective tissue, and highly vascularized organs (liver, heart, lung, and kidney) and that the rate of elimination of radioactivity from tissues was similar to that found in the serum. The apparent elimination half-life of etodolac averaged 17 hr in rats, 10 hr in dogs, and 7 hr in man. Etodolac was extensively bound to serum proteins. Liver microsomal cytochrome P-450 levels were unaltered in rats given etodolac daily for 1 week. The primary route of excretion in rats and dogs was via the bile into the feces. Preliminary biotransformation studies in dogs showed the presence of the glucuronide conjugate of etodolac in bile, but not in the urine. Glucuronide conjugates were not seen in the rat. Four hydroxylated metabolites in rat bile were tentatively identified. It was concluded that, in rats and dogs, etodolac is well absorbed, is subject to extensive enterohepatic circulation, undergoes partial biotransformation, and is excreted primarily into the feces.U     

Comparative pharmacokinetics of a new benzamide neuroleptic drug in rats, dogs and monkeys using a stable isotope technique

Comparative pharmacokinetics of a new benzamide neuroleptic drug, cis-N-(1-benzyl-2-methylpyrrolidine-3-yl)-5-chloro-2-methoxy-4-met hylamino benzamide (NBND) was studied in rats, dogs and monkeys using two deuterium-labelled compounds. NBND and 2H3-NBND, which showed no biological isotope effect, were co-administered p.o. and i.v. to rats, dogs and monkeys, and the plasma concentrations of unchanged drugs were simultaneously determined by g.l.c.-chemical ionization mass spectrometry with 2H7-NBND as an internal standard. The plasma half-lives (t1/2 beta) after i.v. administration were 1.6, 4.7 and 2.2 h in rats, dogs and monkeys at a dose of 0.2 mg/kg. Plasma clearances were 4.3, 1.7 and 1.4 l/h per kg in rats, dogs and monkeys. Absorption rate constants (Kab) were 1.1, 0.58 and 0.54 per h in rats, dogs and monkeys, at doses of 10, 3 and 5 mg/kg, respectively. Absolute bioavailabilities were 0.8, 9.5 and 1.3% in rats, dogs and monkeys, suggesting that all these species showed large first-pass effects, probably due to hepatic metabolism.     

Pharmacokinetics and disposition of a novel NMDA glycine site antagonist (UK-240,455) in rats,dogs and man

1. UK-240,455 ((+) 6,7-dichloro-5-[N-(2-hydroxyethyl)methanesulphonamido]-2,3 (1H,4H)-quinoxalinedione) is a potent, selective N-methyl D-aspartate (NMDA) glycine site antagonist that is being evaluated for the potential treatment of stroke. 2. UK-240,455 is predominately excreted unchanged in urine (58-68%) in rats, dogs and man following intravenous administration. The remainder of the dose is excreted unchanged in the faeces. It is considered that UK-240,455 is predominantly cleared by active renal tubular secretion and active hepatobiliary transport. In man, there is evidence that UK-240,455 undergoes glucuronidation. However, there is no evidence for this in rats and dogs. 3. UK-240,455 has a short elimination half-life in rats, dogs and man (0.4-1.4 h) and clearances of 12, 13 and 6 ml min(-1) kg(-1), respectively. The compound shows limited tissue distribution with volumes of distribution of 0.4-0.8 l kg(-1) in rats, dogs and man. The species' variation in pharmacokinetic parameters was related allometrically when plasma protein binding was taken in to account. Hence, active hepatic or renal clearance processes for this compound were conserved across species. 4. Cerebrospinal fluid and brain concentrations of UK-240,455 were determined in rats. The cerebrospinal fluid/plasma concentration ratio of UK-240,455 was 4.3%, which was similar to the plasma-free fraction of this compound (3%), indicating good blood-brain barrier permeability. Brain tissue concentrations were low (0.7% of the total plasma concentrations).     

The comparative disposition and metabolism of dolutegravir,a potent HIV-1 integrase inhibitor,in mice,rats, and monkeys

Abstract

1.?Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12?mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28?L/kg, respectively) with terminal elimination half-life approximately 6?h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension.

2.?Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species.

3.?Following oral administration to rats, [¹⁴C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24?h.

4.?The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.     

Pharmacokinetics and disposition of a novel NMDA glycine site antagonist (UK-240,455) in rats,dogs and man

1. UK-240,455 ((+) 6,7-dichloro-5-{ N- (2-hydroxyethyl)methanesulphonamido}-2,3 (1H,4H)-quinoxalinedione) is a potent, selective N- methyl D-aspartate (NMDA) glycine site antagonist that is being evaluated for the potential treatment of stroke. 2. UK-240,455 is predominately excreted unchanged in urine (58-68%) in rats, dogs and man following intravenous administration. The remainder of the dose is excreted unchanged in the faeces. It is considered that UK-240,455 is predominantly cleared by active renal tubular secretion and active hepatobiliary transport. In man, there is evidence that UK-240,455 undergoes glucuronidation. However, there is no evidence for this in rats and dogs. 3. UK-240,455 has a short elimination half-life in rats, dogs and man (0.4-1.4?h) and clearances of 12, 13 and 6 ml?min ? 1 kg ? 1, respectively. The compound shows limited tissue distribution with volumes of distribution of 0.4-0.8?l kg ? 1 in rats, dogs and man. The species' variation in pharmacokinetic parameters was related allometrically when plasma protein binding was taken in to account. Hence, active hepatic or renal clearance processes for this compound were conserved across species. 4. Cerebrospinal fluid and brain concentrations of UK-240,455 were determined in rats. The cerebrospinal fluid/plasma concentration ratio of UK-240,455 was 4.3%, which was similar to the plasma-free fraction of this compound (3%), indicating good blood-brain barrier permeability. Brain tissue concentrations were low (0.7% of the total plasma concentrations).     

The metabolic disposition of acifran, a new antihyperlipidemic agent, in rats and dogs

The metabolic disposition of the antihyperlipidemic agent acifran (AY-25, 712) was determined in rats and dogs. The synthesis of 14C-labelled acifran is described. Serum levels of 14C and acifran were measured in rats and dogs after p.o. and i.v. administration of 14C-acifran at a dose of 10 mg/kg. Over 80% of the 14C in serum was due to acifran. The drug was rapidly absorbed and the pharmacokinetics, unaffected by increasing the dose or by daily multiple doses, were characterized by a two-compartment open model. Food reduced the bioavailability of acifran by 27% in the dog. About 65% of the dose was absorbed in rats, and at least 88% in dogs. The elimination t 1/2 of acifran from serum was 1.5 h in the rat and 3 h in the dog. Acifran was partially bound to serum proteins, man greater than rat greater than dog; the drug was found to displace protein-bound warfarin in rat and dog, but not in human serum. Radioactivity did not tend to accumulate in tissues, except for the kidney, where the 14C concentration was five times higher than in the serum; elimination of 14C from all the tissues was similar to that from serum. Most of the absorbed dose was excreted in the urine. Acifran did not undergo enterohepatic circulation in the rat. Virtually all the urinary 14C in both species was due to the unchanged compound. In conclusion, the disposition of acifran was similar in rats and dogs. The drug was rapidly absorbed and eliminated, and underwent no detectable biotransformation. There was no tissue retention and excretion was mainly in the urine.