Pharmacokinetics,metabolism and excretion of the glycine antagonist GV150526A in rat and dog

1. The pharmacokinetics, metabolic fate and excretion of 3-[-2(phenylcarbamoyl) ethenyl-4,6-dichloroindole-2-carboxylic acid (GV150526), a novel glycine antagonist for stroke, in rat and dog following intravenous administration of [C14]-GV150526A were investigated. 2. Studies were also performed in bile duct-cannulated animals to confirm the route of elimination and to obtain more information on metabolite identity. 3. Metabolites in plasma, urine and bile were identified by HPLC-MS/MS and NMR spectroscopy. 4. GV150526A was predominantly excreted in the faeces via the bile, with only trace metabolites of radioactivity in urine (< 5%). Radioactivity in rat bile was predominantly due to metabolites, whereas approximately 50% of the radioactivity in dog bile was due to parent GV150526. 5. The principal metabolites in bile were identified as glucuronide conjugates of the carboxylic acid, whereas in rat urine the main metabolite was a sulphate conjugate of an aromatic oxidation metabolite. Multiple glucuronide peaks were observed and identified as isomeric glucuronides and their anomers arising from acyl migration and muta-rotation.     

Identification of UDP-glucuronosyltransferases involved in the human hepatic metabolism of GV150526, a novel glycine antagonist

The major metabolic pathway for elimination of GV150526 is by glucuronidation exerted by glucuronosyl transferases (UGTs). Potential exists for the modification of GV150526 pharmacokinetics by drugs capable of inhibiting the glucuronidation of GV150526. Using human liver microsomes, 44 compounds were screened for inhibition of GV150526 glucuronidation. These compounds were selected because they are extensively glucuronidated themselves or are used as concomitant medication in the treatment of acute stroke. For 11 compounds out of the 44, full inhibition kinetics were performed to determine their Ki-value and mechanism of inhibition. To predict possible in vivo drug-drug interactions, the theoretical percentage of inhibition (i) was determined, based on in vitro determined Ki-values, and the expected Cmax plasma levels of GV150526 and the inhibitor. Of the 11 compounds examined, only propofol had an i-value of 6.6; for all other compounds i-values were lower than 2.1. These results indicate that although in vitro inhibition is observed, the likelihood of in vivo drug-drug metabolic interactions occurring is low. The inhibition results suggest that in addition to UGT1A1, also UGT1A3, UGT1A8/9, and UGT2B4 are involved in the glucuronidation of GV150526. The involvement of UGT1A1 and UGT1A8/9 was confirmed from studies using cDNA expressed human UGT cell lines.     

Receptor binding characteristics of the novel NMDA receptor glycine site antagonist [3H]GV150526A in rat cerebral cortical membranes

Binding of the glycine site antagonist 3-[2-(Phenylamino-carbonyl)ethenyl]-4,6-dichloro-indole-2-carboxylic acid sodium salt ([3H]GV150526A) was characterised in rat cerebral cortical membranes. Saturation experiments indicated the existence of a high affinity binding site, with a pK(d) value of 9.08 (K(d)=0. 8 nM) and a B(max) of 3.4 pmol/mg of protein. A strong linear correlation was observed between the displacement potencies for [3H]GV150526A and [3H]glycine of 13 glycine site ligands (r=0.991). The association kinetics of [3H]GV150526A binding was monophasic, with a k(on) value of 0.047 (nM)(-1) min(-1). Dissociation was induced by the addition of an excess of glycine, GV150526A, or 5,7-dichlorokynurenic acid (DCKA), another glycine antagonist. With GV150526A and DCKA, the dissociation curves presented similar k(off) values (0.068 and 0.069 min(-1), respectively), as expected from ligands binding to the same site. Conversely, a significantly lower k(off) value (0.027 min(-1)) was found with glycine. Although these data may suggest that glycine agonists and antagonists bind to discrete sites with an allosteric linkage (rather than interacting competitively), the reason for this difference remains to be elucidated. It is concluded that [3H]GV150526A can be considered a new valuable tool to further investigate the properties of the glycine site of the NMDA receptor.     

The neuroprotective glycine receptor antagonist GV150526 does not produce neuronal vacuolization or cognitive deficits in rats.

The neuroprotective activity of the novel glycine receptor antagonist (E)-3[(phenylcarbamoil)ethenil]-4,6-dichloroindole-2-c arboxylic acid sodium salt) (GV150526) was recently reported in a model of focal ischemia in the rat. Here it was investigated whether GV150526 treatment results in any of the adverse side effects commonly detected after injection of NMDA (N-methyl-D-aspartate) receptor antagonists. First, it was found that neuronal vacuolization in the posterior cingulate/retrosplenial area of the cortex was not induced by GV150526 (200 mg/kg, i.v.), but was evident after injection of the NMDA receptor antagonist dizocilpine (MK801) (1 mg/kg, s.c.). In a second set of experiments, the effects of GV150526 were examined on perforant path-dentate gyrus long-term potentiation in rats. GV150526 (3 mg/kg, i.v.) injected 30 min or 150 min prior to tetanization did not block potentiation of the e.p.s.p. slope and population spike amplitude. In contrast, in animals treated with MK801 (1 mg/kg, i.p.) 150 min before tetanization there was a clear block of long-term potentiation of the e.p.s.p. slope and population spike amplitude. The effects of GV150526 were also examined in the Morris Water Maze. Rats injected with GV150526 (10 mg/kg or 60 mg/kg, p.o.) did not show any impairment in learning when compared to control. MK801 (0.08 mg/kg, i.p.), on the other hand, significantly affected the ability to locate the escape platform in the Water Maze. These findings show that GV150526 is devoid of adverse side effects even at doses well above those producing a neuroprotective effect. This, drug has therapeutic potential with a much greater margin of safety than NMDA channel blockers or competitive NMDA receptor antagonists.     

The neuroprotective activity of the glycine receptor antagonist GV150526: an in vivo study by magnetic resonance imaging.

The neuroprotective activity of GV150526 (3-[2-(Phenylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt), a selective glycine receptor antagonist of the NMDA receptor, has been evaluated by magnetic resonance imaging (MRI) in a rat model of middle cerebral artery occlusion. The aim of the work was to evaluate, using an in vivo method, whether GV150526 was able to reduce the extent of ischemic brain damage when administered both before and after (6 h) middle cerebral artery occlusion. GV150526 was administered at a dose of 3 mg/kg i.v. T2-weighted (T2W) and diffusion weighted (DW) images were acquired at 6, 24 and 144 h after the establishment of the cerebral ischemia. Substantial neuroprotection was demonstrated at all investigated time points when GV150526 was administered before the ischemic insult. The ischemic volume was reduced by 84% and 72%, compared to control values, when measured from T2W and DW images, acquired 24 h after middle cerebral artery occlusion. Administration of the same dose of GV150526, 6 h post-ischemia, also resulted in a significant (p < 0.05) neuroprotection. The ischemic volume was reduced by 48% from control values when measured from T2W images and by 45% when measured from DW images. No significant difference was found between volumes of brain ischemia obtained by either MRI or triphenyltetrazolium chloride staining. These data confirm the potential neuroprotective activity of the glycine receptor antagonist GV150526 when administered either before or up to 6 h after ischemia.     

Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat, dog and human

1. UK-224,671 is a sulphamide-containing NK2 antagonist with moderate lipophilicity and basicity. 2. The physicochemical properties of UK-224,671 are reflected in its pharmacokinetics following intravenous (i.v.) administration. The compound partitioned extensively into red blood cells in all species examined and the blood clearance was moderate to low with respect to liver blood flow and distribution into tissues was extensive. 3. UK-224,671 exhibited species differences in oral bioavailability. In dog, the compound exhibited moderate bioavailability (55%), whereas in rat and man oral bioavailability was < 10%. 4. In rat and dog, the major excreted form after i.v. administration was unchanged UK-224,671 in both urine and faeces. In addition, of three metabolites observed, the most abundant was the N-descyclopropylmethyl (UK-280,045). 5. The profile of radioactivity in rat following oral administration of [14C]-UK-224,671 was not consistent with a 10% absorbed compound with 40% of the dose present as metabolites. This suggests that the low bioavailability of UK-224,671 in rat is due to a combination of moderate intestinal permeability and extensive first-pass metabolism by the gut and does not result from poor gastrointestinal absorption per se.     

Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat,dog and human

1. UK-224,671 is a sulphamide-containing NK₂ antagonist with moderate lipophilicity and basicity. 2. The physicochemical properties of UK-224,671 are reflected in its pharmacokinetics following intravenous (i.v.) administration. The compound partitioned extensively into red blood cells in all species examined and the blood clearance was moderate to low with respect to liver blood flow and distribution into tissues was extensive. 3. UK-224,671 exhibited species differences in oral bioavailability. In dog, the compound exhibited moderate bioavailability (55%), whereas in rat and man oral bioavailability was &lt; 10%. 4. In rat and dog, the major excreted form after i.v. administration was unchanged UK224,671 in both urine and faeces. In addition, of three metabolites observed, the most abundant was the N-descyclopropylmethyl (UK-280,045). 5. The profile of radioactivity in rat following oral administration of [¹⁴C]-UK-224,671 was not consistent with a 10% absorbed compound with 40% of the dose present as metabolites. This suggests that the low bioavailability of UK-224,671 in rat is due to a combination of moderate intestinal permeability and extensive first-pass metabolism by the gut and does not result from poor gastrointestinal absorption per se.     

Pharmacokinetics,toxicokinetics, distribution,metabolism and excretion of linezolid in mouse,rat and dog

1. Linezolid (ZYVOX?), the first of a new class of antibiotics, the oxazolidinones, is approved for treatment of Gram-positive bacterial infections. 2. The aim was to determine the absorption, distribution, metabolism and excretion (ADME) of linezolid in mouse, rat and dog in support of preclinical safety studies and clinical development. 3. Conventional replicate study designs were employed in animal experiments, and biofluids were assayed by HPLC or HPLC-MS. 4. Linezolid was rapidly absorbed after p.o. dosing with an p.o. bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day i.v./p.o. toxicokinetic studies in rat (20-200mg kg^?1 day^?1) and dog (10-80mg kg^?1 day^?1) revealed neither a meaningful increase in clearance nor accumulation upon multiple dosing. 5. Linezolid had limited protein binding (<35%) and was very well distributed to most extravascular sites, with a volume of distribution at steady-state (V_ss) approximately equal to total body water. 6. Linezolid circulated mainly as parent drug and was excreted mainly as parent drug and two inactive carboxylic acids, PNU-142586 and PNU-142300. Minor secondary metabolites were also characterized. In all species, the clearance rate was determined by metabolism. 7. Radioactivity recovery was essentially complete within 24-48h. Renal excretion of parent drug and metabolites was a major elimination route. Parent drug underwent renal tubular reabsorption, significantly slowing parent drug excretion and allowing a slow metabolic process to become rate-limiting in overall clearance. 8. It is concluded that ADME data were relatively consistent across species and supported the rat and dog as the principal non-clinical safety species.     

Pharmacokinetics,toxicokinetics, distribution,metabolism and excretion of linezolid in mouse,rat and dog

1. Linezolid (ZYVOX), the first of a new class of antibiotics, the oxazolidinones, is approved for treatment of Gram-positive bacterial infections. 2. The aim was to determine the absorption, distribution, metabolism and excretion (ADME) of linezolid in mouse, rat and dog in support of preclinical safety studies and clinical development. 3. Conventional replicate study designs were employed in animal experiments, and biofluids were assayed by HPLC or HPLC-MS. 4. Linezolid was rapidly absorbed after p.o. dosing with an p.o. bioavailability of > 95% in rat and dog, and > 70% in mouse. Twenty-eight-day i.v./p.o. toxicokinetic studies in rat (20-200mg kg(-1) day(-1)) and dog (10-80 mg kg(-1) day(-1)) revealed neither a meaningful increase in clearance nor accumulation upon multiple dosing. 5. Linezolid had limited protein binding (<35%) and was very well distributed to most extravascular sites, with a volume of distribution at steady-state (V(ss)) approximately equal to total body water. 6. Linezolid circulated mainly as parent drug and was excreted mainly as parent drug and two inactive carboxylic acids, PNU-142586 and PNU-142300. Minor secondary metabolites were also characterized. In all species, the clearance rate was determined by metabolism. 7. Radioactivity recovery was essentially complete within 24-48 h. Renal excretion of parent drug and metabolites was a major elimination route. Parent drug underwent renal tubular reabsorption, significantly slowing parent drug excretion and allowing a slow metabolic process to become rate-limiting in overall clearance. 8. It is concluded that ADME data were relatively consistent across species and supported the rat and dog as the principal non-clinical safety species.     

Pharmacokinetics and metabolism of gabapentin in rat, dog and man

This paper describes the pharmacokinetic studies of 1-(aminomethyl)-cyclohexane acetic acid (gabapentin, G? 3450, CI-945) conducted with the 14C-labelled substance following intravenous and intragastric administration to rats and dogs and oral administration to humans. Gabapentin is well absorbed in rats, dogs and in humans, with maximum blood levels, reached within 1-3 h after peroral administration. Following i.v. administration to rats, similar blood and brain levels of gabapentin are observed after a short distribution phase, whereby concentrations in cerebrum and cerebellum are comparable. The highest concentrations are found in the pancreas and kidneys and the lowest values in adipose tissue. No binding of gabapentin to human plasma proteins or human serum albumin is observed. The distribution coefficient (octanol/buffer pH 7.4) is 7.5 X 10(-2). In man, no biotransformation of gabapentin is observed. In rats, biotransformation is only minor. In dogs, however, a remarkable formation of N-methyl-gabapentin is found. Elimination half-lives range between 2-3 h in rats, 3-4 h in dogs, and 5-6 h in man. Gabapentin is nearly exclusively eliminated via the kidneys. Renal elimination was up to 99.8% in rats and approx. 80% in man following oral administration. The blood level-time course after i.v. administration to rats can well be described by a three-compartment open model. Experiments in rats and dogs demonstrate that pharmacokinetics are not sex-dependent and are not changed after multiple dosage. Pharmacokinetics are shown to be linear in the range tested of 4 to 500 mg/kg i.v. in rats.     

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the dog.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in dogs and also eliminated rapidly with a short half-life. Following single intravenous doses, dexloxiglumide was characterised as a drug having a high clearance (30.7 and 27.0 ml/min/kg in males and females respectively), a low volume of distribution (Vss, 0.34 and 0.27 L/kg in males and females respectively) and a moderate systemic availability (about 33%). It was extensively bound to plasma proteins (89%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the kidney, liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. 14C concentrations generally peaked at 0.25h and declined rapidly during 24h being present only in a few tissues (such as the kidney, liver and gastrointestinal tract) at 24h. Single intravenous or oral doses were mainly excreted in the faeces (77-89%), mostly during 24h. Urine contained up to 7.5% dose. Mean recoveries during 7 days ranged between 93-97%. Biliary excretion of 14C was prominent (64% dose during 24h) in the disposition of 14C which was probably also subjected to some limited enterohepatic circulation. Unchanged dexloxiglumide was the major component in plasma. Urine and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. about 55% dose in faeces). LC-MS/MS of urine and bile extracts showed that dexloxiglumide was metabolised mainly by O-demethylation and by conjugation with glucuronic acid.     

Substituted analogues of GV150526 as potent glycine binding site antagonists in animal models of cerebral ischemia.

A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4, 6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant neuroprotective effect was seen in this model postischaemia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.     

Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man.

1. Pharmacokinetics of dofetilide were studied in man, dog, rat and mouse after single i.v. and oral doses of dofetilide or 14C-dofetilide. 2. Dofetilide was absorbed completely in all species. Low metabolic clearance in man resulted in complete bioavailability following oral administration. Higher metabolic clearance in rodents, and to a lesser extent dogs, resulted in decreased bioavailability because of first-pass metabolism. 3. Following i.v. administration, the volume of distribution showed only moderate variation in all species (2.8-6.3 l/kg). High plasma clearance in rodents resulted in short half-life values (mouse 0.32, male rat 0.5 and female rat 1.2 h), whilst lower clearance in dog and man gave longer terminal elimination half-lives (4.6 and 7.6 h respectively). 4. After single i.v. doses of 14C-dofetilide, unchanged drug was the major component excreted in urine of all species with several metabolites also present. 5. Metabolites identified in urine from all species were formed by N-oxidation or N-dealkylation of the tertiary nitrogen atom of dofetilide. 6. After oral and i.v. administration of 14C-dofetilide to man, parent compound was the only detectable component present in plasma and represented 75% of plasma radioactivity. No single metabolite accounted for greater than 5% of plasma radioactivity.     

Pharmacokinetics, bioavailability, metabolism, tissue distribution and urinary excretion of gamma-L-glutamyl-L-dopa in the rat

gamma-L-Glutamyl-L-dopa (gludopa) is believed to be a dopamine prodrug specific for the kidney. Its pharmacokinetics have been studied in the rat given 50 mg kg-1 intravenously (i.v.) and 60 mg kg-1 intraperitoneally (i.p.). By the i.v. route, elimination followed apparent first order kinetics and was biphasic with a t 1/2 alpha of 7 min and terminal half-life of 67 min. After i.p. administration absorption was rapid (t 1/2 ab 6 min), elimination was monophasic with a terminal half-life almost identical following i.v. dosing (65 min), and bioavailability was 40%. In tissues (liver and kidney) gludopa was biotransformed to four intact catecholic products (L-dopa, dopamine, DOPAC and gamma-L-glutamyl-dopamine) which appeared quickly (peaks at 15 min) and which were almost completely cleared by 4 h. Dopamine was the major kidney metabolite accounting for 69% of total catechol content with an AUC 31 times greater than in liver where it accounted for only 34% of total catechols. In rat urine eight major metabolites (5.7% of the dose) and at least 12 minor metabolites were detected of all of which 85% was dopamine. A higher percentage of the dose was excreted as intact catechols in man (15.7%) but fewer metabolites were detected (L-dopa, dopamine, DOPAC). It is confirmed that gludopa is kidney specific in rat but that the pharmacological effects of dopamine are likely to be short lived due to rapid clearance. Gludopa appears to be less dopamine specific in man.     

Absorption,metabolism and excretion studies on clavulanic acid in the rat and dog

1. At least one third of an oral dose of sodium [G-¹⁴C]clavulanate was absorbed by rat and dog. Excretion of radioactivity was rapid in both species.

2. In addition to urinary and faecal excretion of radioactivity, appreciable elimination of ¹⁴CO₂ occurred, particularly in the rat. This was produced in part by the action of the gut microflora.

3. In the rat, only a small proportion of the radioactive dose was secreted in the bile.

4. The major metabolite in urine was identified as l-amino-4-hydroxybutan-2-one. Clavulanic acid was also a major component in urine.     

Pharmacokinetics and metabolism of inhaled methyl chloride in the rat and dog

Methyl chloride (MeCl) metabolism and pharmacokinetics were studied in male Fischer 344 rats and male beagle dogs. Apparent steady-state blood MeCl concentrations were proportionate to exposure concentration in rats and dogs exposed to 50 and 1000 ppm. Furthermore, blood MeCl concentrations were similar in both species when they were exposed to the same concentration. A linear two-compartment open model described the blood MeCl data: α and β phase elimination half-times corresponded to approximately 4 and 15 min, respectively, in rats, and 8 and 40 min in dogs. Rats exposed for 6 hr to 0, 50, 225, 600, or 100 [¹⁴C]MeCl were evaluated for tissue nonprotein sulfhydryl (NPSH), total ¹⁴C activity, nonextractable tissue ¹⁴C activity, and urinary metabolites. MeCl-induced NPSH depletion was dose-related and was greates in liver. Total ¹⁴C in liver and kidney was approximately proportionate to exposure concentrations. Relative concentrations of nonextractable ¹⁴C decreased at 600 to 1000 ppm MeCl suggesting a dose-dependent metabolic pathway for MeCl in the rat. Metabolites in urine included N-acetyl-S-methylcysteine, methylthioacetic acid sulfoxide, and N-(methylthioacetyl)glycine. These metabolites are likely to be products of a reaction between MeCl and glutathione. A nonradiometric analysis of a putative MeCl metabolite (S-methylcysteine) was performed in dogs exposed to MeCl; this method was not a sensitive indicator of MeCl exposure.     

Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man

1. Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after single intravenous and/or oral doses of sildenafil or [14C]-sildenafil (Viagra). 2. In man, absorption from the gastrointestinal tract was essentially complete. With the exception of male rat, Tmax occurred at approximately 1 h or less. Bioavailability was attenuated by pre-systemic hepatic metabolism in all species. 3. The volume of distribution was similar in rodents and humans (1-2 l/kg) but was greater in dog (5.2 l/kg), due to lower plasma protein binding (84 versus 94-96% respectively). 4. High clearance was the principal determinant of short elimination half-lives in rodents (0.4-1.3 h), whereas moderate clearance in dog and man resulted in longer half-lives (6.1 and 3.7 h respectively). Clearances were in agreement with in vitro metabolism rates by liver microsomes from the various species. 5. After single oral or intravenous doses of [14C]-sildenafil, the majority of radioactivity was excreted in the faeces of all species. No unchanged drug was detected in the excreta of man. 6. Five principal pathways of metabolism in all species were piperazine N-demethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring and aliphatic hydroxylation. Additional metabolites arose through combinations of these pathways. 7. Sildenafil was the major component detected in human plasma. Following oral doses, AUC(infinity) for the piperazine N-desmethyl and piperazine N,N'-desethyl metabolites were 55 and 27% that of parent compound respectively.     

Absorption, distribution and excretion of lacidipine, a dihydropyridine calcium antagonist, in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog). 2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism. 3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug. 4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species. 5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses. 6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration. 7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

Pharmacokinetics, metabolism and excretion of an inhibitor of inducible nitric oxide synthase, L-NIL-TA, in dog

1. The pharmacokinetics, metabolism and excretion of L-NIL-TA, an inducible nitric oxide synthase inhibitor, were investigated in dog. 2. The dose of [14C]L-NIL-TA was rapidly absorbed and distributed after oral and intravenous administration (5 mg kg-1), with Cmax of radioactivity of 6.45-7.07 microg equivalents g-1 occurring at 0.33-0.39-h after dosing. After oral and intravenous administration, radioactivity levels in plasma then declined with a half-life of 63.1 and 80.6-h, respectively. 3. Seven days after oral and intravenous administrations, 46.4 and 51.5% of the radioactive dose were recovered in urine, 4.59 and 2.75% were recovered in faeces, and 22.4 and 22.4% were recovered in expired air, respectively. The large percentages of radioactive dose recovered in urine and expired air indicate that [14C]L-NIL-TA was well absorbed in dogs and the radioactive dose was cleared mainly through renal elimination. The mean total recovery of radioactivity over 7 days was approximately 80%. 4. Biotransformation of L-NIL-TA occurred primarily by hydrolysis of the 5-aminotetrazole group to form the active drug L-N6-(1-iminoethyl)lysine (NIL or M3), which was further oxidized to the 2-keto acid (M5), the 2-hydroxyl acid (M1), an unidentified metabolite (M2) and carbon dioxide. The major excreted products in urine were M1 and M2, representing 22.2 and 21.2% of the dose, respectively.