PHARMACOKINETICS AND TOXICOKINETICS OF AN ORALLY ACTIVE TRIPEPTIDE,IRI-695, IN ANIMALS

Pharmacokinetics and toxicokinetics of IRI-695, a tripeptide, were investigated in the rat, rabbit, dog, and monkey. Tissue distribution and excretion of [¹⁴C]IRI-695 were determined in the rat. Following a single intravenous (IV) injection, the elimination half-life (t_1/2) of IRI-695 in the rabbit, dog, and monkey was similar (about 65 min) and approximately four times that in the rat (15 min). This difference in t_1/2 can be attributed to about four times higher clearance of the drug in rats (11·2 mL min⁻¹ kg ⁻¹). The volume of distribution (V_ss) in these four species, 132–234 mL kg⁻¹, suggested negligible preferential distribution of IRI-695 to body tissue. After a 5 mg kg⁻¹ oral dose, the absolute bioavailability of IRI-695 was 2·0% in rats and 3·1% in dogs. However, systemic drug exposure in the dog was about five to 10 times that in the rat, which is related to the slower clearance of the peptide in the dog. Toxicokinetic studies in the rat and dog indicated linear kinetics and systemic exposure of IRI-695 up to 300 mg kg⁻¹ d⁻¹ oral doses throughout the 28 d toxicity study. Accumulation of the drug after the repeated oral dosing was negligible. After a single 0·10 mg kg⁻¹ ]¹⁴C[IRI-695 IV injection in rats, almost all of the radioactivity administered was excreted in urine within 24 h postdose.     

Metabolism and disposition of 14C-granisetron in rat,dog and man after intravenous and oral dosing

1. The disposition and metabolic fate of ¹⁴C-granisetron, a novel 5-HT₃ antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration.

2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species.

3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0·25 and 5 mg/kg in rat and 0·25 and 10mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man.

4. In rat and dog, 35–41% of the dose was excreted in urine and 52–62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5–25% of dose).

5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.     

Comparison of celecoxib metabolism and excretion in mouse,rabbit, dog,cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit,the EM(extensive) and PM(poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [¹⁴C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [¹⁴C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.     

Pharmacokinetics of the novel,high-affinity and selective dopamine D3 receptor antagonist SB-277011 in rat,dog and monkey: in vitro/in vivo correlation and the role of aldehyde oxidase

1. In vitro studies with the selective dopamine D3 receptor antagonist SB-277011 were conducted in liver microsomes and homogenates from rat, dog, cynomolgus monkey and human to correlate the rate of metabolism with the in vivo pharmacokinetics of the compound in rat, dog and cynomolgus monkey. 2. In the presence of NADPH, SB-277011 was relatively stable in the presence of liver microsomes from rat, dog, cynomolgus monkey and human with an intrinsic clearance (CL_i) of <2ml min^-1 g^-1 liver for all species. In total liver homogenates, SB-277011 was metabolized at a similar rate in rat and dog (CL_i <2mlmin^-1 g^-1 liver) to that in liver microsomes but in cynomolgus monkey and human (CL_i = 9.9 and 45 mlmin ^-1 g-^-1 liver, respectively) the intrinsic clearance was ~6- and 35-fold higher, respectively, than that in liver microsomes. 3. In the absence of NADPH, SB-277011 was rapidly cleared in liver homogenates from cynomolgus monkey and human (CL_i = 7.4 and 27ml min^-1 g^-1 liver, respectively) demonstrating that a significant pathway of metabolism of this compound was via an NADPH-independent non-microsomal oxidative route. This pathway was sensitive to inhibition with isovanillin suggesting that the enzyme responsible was aldehyde oxidase. 4. The in vivo pharmacokinetics showed that the plasma clearance of SB-277011 was low in rat (20 mlmin^-1 kg^-1), moderate in dog (14 mlmin^-1 kg^-1) and high in cynomolgus monkey (58 mlmin^-1 kg^-1), which is consistent with the in vitro findings and demonstrated a greater capacity for the monkey to metabolize this compound. The oral bioavailability of SB-277011 in rat, dog and cynomolgus monkey was 35, 43 and 2%, respectively. Given the high clearance of this compound in cynomolgus monkey, the low oral bioavailability is probably as a result of high first-pass elimination, specifically by aldehyde oxidase, rather than poor absorption. 5. The high in vitro clearance of SB-277011 in human liver homogenates and the involvement of aldehyde oxidase in the metabolism of SB-277011 indicates that the bioavailability of the compound is likely to be low in human.     

The Metabolism of Terbutaline in Dog and Rat

Abstract

1. The metabolic fate of [³H]terbutaline has been studied in dog after oral, intravenous and subcutaneous administration and in rat after oral and intravenous administration. In 3–4 days the dog excreted 75% of the dose in the urine after oral administration and more than 90% after intravenous or subcutaneous administration; the remainder was in the faeces. The rat in 24 h excreted about 13% in the urine and 61% in the faeces after oral administration and 48% in the urine and 35% in the faeces after intravenous administration.

2. After oral administration of [³H]terbutaline, the time course of radioactivity concentration was the same in lung, heart and serum; low levels of unchanged drug were found in all tissues. After intravenous administration, the concentration of unchanged drug was higher in lung and heart than in serum.

3. In dog, 1·7% of an intravenous dose was excreted into bile in 6 h. In rat, about 37% of the dose was recovered in the bile during 12 h.

4. Enzymic hydrolysis of urine showed that terbutaline is metabolized by conjugation, forming a glucuronide in rat but probably a sulphate in dog.     

Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing

The pharmacokinetics of a new serotonin 5-HT₂ antagonist, deramciclane, was studied. Single oral doses of 1, 3, 6 and 10 mg kg⁻¹ and intravenous doses of 1, 3 and 6 mg kg⁻¹ were administered in beagle dogs. Moreover, the steady state pharmacokinetics of 1, 3 and 6 mg kg⁻¹ doses were studied. Deramciclane was rapidly and completely absorbed from the gastrointestinal tract. Due to a moderate first-pass metabolism the absolute bioavailability was only 45–61%. Deramciclane had a large volume of distribution (32–37 L kg⁻¹) because of its lipophilic nature. Deramciclane was extensively metabolized after intravenous injection and only trace amounts of intact drug is excreted in the urine. The total body clearance decreased (from 32 to 17 L h⁻¹) as the dose increased. It is suggested that the metabolic capacity was not sufficient to eliminate deramciclane in a linear manner with increasing dose. Therefore, deramciclane exhibited nonlinear pharmacokinetics as the AUC_0–∞ increased disproportionally to the dose after both intravenous and oral dosing. Formation of the active metabolite, N-desmethyl deramciclane, was also nonlinear (p =0.0002). At steady state deramciclane accumulated less than 2-fold during repeated administration. Copyright © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics of a new reversible proton pump inhibitor,YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5–20 mg kg⁻¹, to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50–200 mg kg⁻¹, to rats, the area under the plasma concentration–time curve from time zero to 12 or 24 h (AUC_{0–12 h} or AUC_{0–24 h}) was proportional to the oral dose of the drug, 50–100 mg kg⁻¹, however, the AUC_{0–24 h} value at 200 mg kg⁻¹ increased with less proportion to the dose increase (324, 689, and 815 μg · min mL⁻¹ for 50, 100, and 200 mg kg⁻¹, respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg⁻¹, respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg⁻¹. The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg⁻¹, was approximately 70% (116 versus 163 μg · min mL⁻¹) of that after iv administration of the drug, 5 mg kg⁻¹, to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5–20 mg kg⁻¹, to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg⁻¹, to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5–20 mg kg⁻¹, to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC_{0–10 h} values were not significantly different (96.8 versus 98.2 μg · min mL⁻¹) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs. Copyright © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics and urinary excretion of DMXBA (GTS-21), a compound enhancing cognition

DMXBA (3-(2, 4-dimethoxybenzylidene)-anabaseine, also known as GTS-21) is currently being tested as a possible pharmacological treatment of cognitive dysfunction in Alzheimer's disease. In this study, plasma and brain pharmacokinetics as well as urinary excretion of this compound have been evaluated in adult rats. DMXBA concentrations were determined by HPLC. Following a 5 mg kg⁻¹ iv dose, DMXBA plasma concentration declined bi-exponentially with mean (±SE) absorption and elimination half-lives of 0.71±0.28 and 3.71±1.12 h, respectively. The apparent steady state volume of distribution was 2150±433 mL kg⁻¹, total body clearance was 1480±273 mL h⁻¹ kg⁻¹, and AUC_0–∞ was 3790±630 ng h mL⁻¹. Orally administered DMXBA was rapidly absorbed. After oral administration of 10 mg kg⁻¹, a peak plasma concentration of 1010±212 ng mL⁻¹ was observed at 10 min after dosing. Elimination half-life was 1.740±0.34 h, and AUC_0–∞ was 1440±358 ng h mL⁻¹. DMXBA peak brain concentration after oral administration was 664±103 ng g⁻¹ tissue, with an essentially constant brain–plasma concentration ratio of 2.61±0.34, which indicates that the drug readily passes across the blood–brain barrier. Serum protein binding was 80.3±1.1%. Apparent oral bioavailability was 19%. Renal clearance (21.8 mL h⁻¹ kg⁻¹) was less than 2% of the total clearance (1480±273 mL h⁻¹ kg⁻¹); urinary excretion of unchanged DMXBA over a 96 h period accounted for only 0.28±0.03% of the total orally administered dose. Our data indicates that DMXBA oral bioavailability is primarily limited by hepatic metabolism. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetic characterization of hydroxylpropyl-β-cyclodextrin-included complex of cryptotanshinone,an investigational cardiovascular drug purified from Danshen (Salvia miltiorrhiza)

1.?The study aimed to investigate the pharmacokinetics of cryptotanshinone in a hydroxylpropyl-β-cyclodextrin-included complex in dogs and rats.

2.?Animals were administrated the inclusion complex of cryptotanshinone and the concentrations of cryptotanshinone and its major metabolite tanshinone IIA were determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.

3.?Cryptotanshinone in inclusion complex was absorbed slowly after an oral dose, and the C_max and AUC_0–t were dose-proportional. The bioavailability of cryptotanshinone in rats was (6.9%?±?1.9%) at 60 mg kg^?1and (11.1%?±?1.8%) in dogs at 53.4 mg kg^?1. The t_1/2 of the compound in rats and dogs was 5.3–7.4 and 6.0–10.0 h, respectively. Cryptotanshinone showed a high accumulation in the intestine, lung and liver after oral administration, while the lung, liver and heart had the highest level following intravenous dose. Excretion data in rats showed that cryptotanshinone and its metabolites were mainly eliminated from faeces and bile, and the dose recovery rate was 0.02, 2.2, and 14.9% in urine, bile, and faeces, respectively.

4.?The disposition of cryptotanshinone in an inclusion complex was dose-independent and the bioavailability was increased compared with that without cyclodextrin used to formulate the drug. Cryptotanshinone was distributed extensively into different organs. Excretion of cryptotanshinone and its metabolites into urine was extremely low, and they were mainly excreted into faeces and bile.     

Pharmacokinetics of muraglitazar (BMS-298585), a dual peroxisome proliferator-activated receptors (PPAR) α and γ activator,in mice,rats, dogs,and monkeys

The pharmacokinetic parameters of muraglitazar, a novel dual-activator of the peroxisome proliferator-activated receptors (PPAR)?α?and γ, were determined in mice, rats, dogs, and monkeys after intravenous and oral administration. In the mouse, rat, and monkey the absolute oral bioavailability of muraglitazar ranged from 64 to 88%, and in the dog oral bioavailability was approximately 18%. The systemic clearance values of muraglitazar in the mouse, rat, dog, and cynomolgus monkey were 1.2, 3.0, 12.3 and 1.2?ml min^?1?kg^?1, respectively. The terminal elimination half-life was 2.4?h in dogs and 7.3?h in rats. The terminal elimination half-life could not be determined in the mouse and monkey because the sampling interval did not adequately cover the terminal elimination phase. Muraglitazar appears to be distributed outside of the vasculature, with the steady-state volume of distribution being approximately twofold that of the vascular volume in rats and dogs, and approximately twofold that of the total body water in mice. The systemic plasma clearance of muraglitazar in humans was predicted to be approximately 12–14?ml?min^?1?kg^?1 based on allometry or by scaling of in vitro clearance parameters. Overall, the pharmacokinetic parameters of muraglitazar in preclinical species were acceptable for the advancement of the compound as a clinical candidate.     

The metabolism of bifluranol by rat,dog and ferret

The synthesis of monohydroxy- and dihydroxy-bifluranol, and of glucuronide and sulphate conjugates of bifluranol are described. Bifluranol administered orally to rats, ferrets and dogs at a dosage of 50 to 200 μg kg^?1 is mostly excreted in the faeces as unchanged bifluranol and bifluranol monosulphate, disulphate and monoglucuronide. The bifluranol is well absorbed and is mostly excreted in the bile, as six different conjugates, including a glucuronide sulphate found in all 3 species, and a glucuronide phosphate found only in ferret and dog bile. Hydroxylation of the aromatic rings occurs in the rat, to an extent of about 8% of the dose, but was not detected in ferret or dog.     

THE PHARMACOKINETICS OF 1954U89, 1, 3-DIAMINO-7-(1-ETHYLPROPYL)-8-METHYL-7H-PYRROLO-(3, 2-f )QUINAZOLINE,IN DOGS AND RATS AFTER INTRAVENOUS AND ORAL ADMINISTRATION

1954U89, 1, 3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3, 2-f )quinazoline, is a potent, lipid-soluble inhibitor of dihydrofolate reductase. The pharmacokinetics and bioavailability of 1954U89 were examined in male beagle dogs and male CD rats. Dogs received single intravenous (2·5 mg kg⁻¹) and oral (5·0 mg kg⁻¹) doses of 1954U89 with and without successive administration of calcium leucovorin. Single intravenous (5·0 mg kg⁻¹) and oral (10 mg kg⁻¹) doses of [1,3-¹⁴C₂]1954U89 were administered to rats. Plasma concentrations of total radiocarbon were determined by scintillation counting, and intact 1954U89 was measured by HPLC. The mean plasma half-life was 3·2 ± 0·62 and 4·2 ± 0·68 h after intravenous and oral administration, respectively, to dogs. The pooled plasma half-life after intravenous administration to rats averaged 1·2 h; a reliable plasma half-life value after oral administration could not be determined. Mean total-body clearance was 2·4 ± 0·39 and 4·5 ± 1·1 L h⁻¹ kg⁻¹ after intravenous and oral administration, respectively, to dogs, and averaged 12 and 77 L h⁻¹ kg⁻¹ after intravenous and oral administration, respectively, to rats. Neither clearance nor bioavailability of 1954U89 in dogs was affected significantly by administration of calcium leucovorin. Absolute bioavailability was 54 ± 12% in dogs and 16% in rats. © 1997 John Wiley & Sons, Ltd.     

A pharmacokinetic evaluation of HIV protease inhibitors,cyclic ureas,in rats and dogs

The pharmacokinetics of a series of novel cyclic, non-peptide inhibitors of HIV protease were studied in rats or dogs after intravenous and oral administration. Six symmetrically substituted cyclic urea compounds (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively inhibited HIV virus replication, with IC₉₀, values of 0.03–1.0 μM (0.017–0.76 μg mL^?1), were evaluated. Plasma concentrations were measured in rats and dogs using specific and sensitive HPLC methods. In rats, the maximum plasma concentrations of 0.21–1.88 μg mL^?1 were detected within 1 h of oral administration of 10 mg kg^?1 of the compounds. The elimination half-lives ranged from 1.25 to 3.3 h in rats and the absolute oral bioavailability ranged from 18 to 100%. In dogs, the maximum plasma concentration and absolute oral bioavailability were 4.37 μg mL^?1 and 48%, 1.07 μg mL^?1 and 16%, and 1.48 mg mL^?1 and 38% for XK234, XM311, and XM323, respectively. The data demonstrated that the maximum plasma concentrations of these cyclic ureas were several times higher than the IC₉₀ for inhibition of viral replication after single doses of 10 mg kg^?1 in rats and dogs. With this combination of high potency against virus replication and good oral bioavailability, these cyclic ureas represent a new class of compounds that are suitable for development as therapeutic agents for the treatment of HIV-associated diseases.     

Disposition of LY333531, a selective protein kinase C β inhibitor,in the Fischer 344 rat and beagle dog

1. Studies were conducted in the Fischer 344 rat and beagle dog to determine the disposition of LY333531 and its equipotent active des-methyl metabolite, LY338522, both potent and selective inhibitors of the β-isozyme of protein kinase C. 2. Male Fischer 344 rats and female beagle dogs received a single 5-mgkg^?1 oral dose of ¹⁴C-LY333531. Urine, faeces, bile and plasma were collected and analysed for ¹⁴C, LY333531 and LY338522. 3. LY333531 was eliminated primarily in the faeces (91% by 120 h in rat, 90% by 96h in dog). Bile contributed the majority of the radioactivity excreted in the faeces in rat (66% in the cannulated bile duct study) and a variable but significant proportion in dog. 4. Pharmacokinetics following a single 5?mg kg^?1 oral dose of ¹⁴C-LY333531 to the male rat produced C_max and AUC_0-∞ for LY333531 of 14.7 ng ml^?1 and 60.8ng h ml^?1, respectively, with a half-life of 2.5 h. LY338522 and total radioactivity showed similar profiles. 5. In the female dog at the same dose, C_max and AUC_0-∞ of LY333531 were higher, producing 245 ± 94 ng ml^?1 and 1419 ± 463ng h ml^?1, respectively, with a half-life of 5.7 h. 6. The data indicate that the disposition of LY333531 is similar in rat and dog.     

Development and application of sensitive HPLC assays for NK3 antagonists in rat plasma

CAM 5500 and CAM 5187 are new nonpeptide tachykinin NK₃ receptor antagonists with different lipophilicity and solubility. We have developed and validated two separate, simple HPLC methods for quantitation of these two compounds in plasma to support oral pharmacokinetic/bioavailability studies in rats. The two compounds in plasma were extracted on cyano SPE cartridges with different washing schemes to optimize extraction efficiency and chromatographic specificity. The analytes and internal standard in the resulting extracts were chromatographed on a C18 HPLC column, using mobile phases containing different phosphate buffer strengths and acetonitrile concentrations. Both compounds were detected using UV. Peak area ratios were proportional over the concentration range of 50–3000 ng ml⁻¹ for CAM 5500, and 100–1500 ng ml⁻¹ for CAM 5187. Stability profiles of both drugs and internal standard in rat plasma at 37°C and in injection solvent at ambient temperature were good. Assay precision, based on quality controls, was <5.6% and 13.4% (%RSD) for CAM 5500 and CAM 5187, respectively. Similarly, assay accuracy for both compounds was within ±7.1% and ±6.0% (%RE), respectively. The HPLC methods were successfully applied to assay samples from two oral bioavailability studies. Oral bioavailability studies were conducted for each compound in rats receiving a PO dose of 20 mg kg⁻¹ or an IV dose of 5 mg kg⁻¹. Despite their difference in lipophilicity and solubility, the absolute oral bioavavilability of CAM 5500 (5.3±4.8%) is similar to that of CAM 5187 (8.8%±3.2%).     

Metabolic fate of the thrombolytic agent benzarone in man: comparison with the rat and dog

1. The metabolic fate of ¹⁴C-benzarone in the rat and dog has been compared to that in human subjects. An oral dose was well-absorbed in all three species. However, the ¹⁴C excretion patterns differed: humans (100 mg) excreted means of 73 and 19% dose in the urine and faeces respectively, whereas the rat (2 mg/kg) and dog (0.5 mg/kg) excreted > 80% in the faeces, mostly during the first 48 h.

2. Much of the faecal ¹⁴C was attributable to ¹⁴C excreted in the bile which amounted to 59% in the 7 h bile collected from an intravenously dosed dog, and a mean of 72% in the 24 h bile of orally dosed rats. Enterohepatic circulation of ¹⁴C was demonstrated in rats.

3. Total ¹⁴C in human plasma reached peak concentrations between 1–2 h and declined relatively rapidly, to about 10% of this value within 24 h. Unchanged benzarone was not detected in plasma (< 25 ng/ml), even after a 400 mg dose, but conjugated benzarone was—accounting for about 10% of the peak concentration of ¹⁴C. In the dog, by contrast, conjugated benzarone accounted for about 50% of the peak concentration of ¹⁴C of 0.96 μg equiv./ml at 1 h. The extent of binding of benzarone to human plasma proteins (> 99%; in vitro was slightly greater than that (> 96%) of total ¹⁴C (ex vivo, representing metabolites).

4. Examination of metabolite profiles by h.p.l.c. suggested that in the rat and dog, at least 70% absorbed dose was eliminated by direct conjugation, whereas in humans at least 70% was hydroxylated before conjugation, mainly with glucuronic acid. Hydroxylation occurred in the benzofuran ring and/or the ethyl side-chain. The principal urinary metabolite in humans was the conjugate(s) of the 1-hydroxylated ethyl side-chain derivative (mean 26% dose).     

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 and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys

The purpose of this study was to characterize CI-992 pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) in sodium deplete monkeys. Panels of monkeys were administered CI-992 as a 1 h intravenous infusions (0.1 and 1 mg kg⁻¹) or as single oral doses (0, 10, 50, and 100 mg kg⁻¹). Mean arterial blood pressure (MABP) was monitored and serial blood samples were collected up to 24 h postdose. Plasma CI-992 concentrations were quantitated by radioimmunoassay. Pharmacokinetic parameters were calculated by noncompartmental methods. PK/PD relationships were assessed by standard methods. Oral bioavailability of CI-992 in the monkeys was <2%; steady-state volume of distribution was 0.67 L kg⁻¹; clearance was 10.4 mL min⁻¹ kg⁻¹. Following oral administration, t_max generally occurred 6–9 h postadministration; plasma CI-992 concentrations increased with increasing dose between 10 and 50 mg kg⁻¹, but did not change appreciably from 50 to 100 mg kg⁻¹. After intravenous administration, change in MABP was correlated with plasma CI-992 concentration through an effect compartment model in which the maximum achievable effect was a 22 mm Hg decrease in MABP; the steady-state concentration which produced half the maximum effect was 11 ng mL⁻¹. Following the 10 mg kg⁻¹ oral dose the maximum decrease in MABP was 19.1 mm Hg; higher doses did not produce greater maximum response but increased the duration of action. In contrast to observations following intravenous administration, a trend for decreasing MABP with increasing plasma CI-992 was not apparent following oral CI-992 administration. © 1998 John Wiley & Sons, Ltd.     

Absorption,distribution, metabolism and excretion of telmesteine,amucolitic agent,in rat

1. The metabolism and disposition of telmesteine, a muco-active agent, have been investigated following single oral or intravenous administration of ¹⁴C-telmesteine in the Sprague–Dawley rat.

2. ¹⁴C-telmesteine was rapidly absorbed after oral dosing (20 and 50mg kg^-1) with an oral bioavailability of > 90% both in male and female rats. The C_max and area under the curve of the radioactivity in plasma increased proportionally to the administered dose and those values in female rats were 30% higher than in male rats.

3. Telmesteine was distributed over all organs except for brain and the tissue/plasma ratio of the radioactivity 30min after dosing was relatively low with a range of 0.1–0.8 except for excretory organs.

4. Excretion of the radioactivity was 86% of the dose in the urine and 0.6% in the faeces up to 7 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 3% for the first 24 h. The unchanged compound mainly accounted for the radioactivity in the urine and plasma.

5. Telmesteine was hardly metabolized in microsomal incubations. A glucuronide conjugate was detected in the urine and bile, but the amount of glucuronide was less than 6% of excreted radioactivity.     

Pharmacokinetics and metabolism of NO-1886, a lipoprotein lipase-promoting agent,in cynomolgus monkey

1. The study was conducted to investigate the pharmacokinetics and metabolism of NO-1886 (diethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) in cynomolgus monkeys.

2. After single intravenous administration of NO-1886 at a dose of 3?mg?kg^?1, the total clearance (CL_tot), area under the plasma concentration–time curve (AUC_0–t), half-life (t_1/2), and volume of distribution (V_d) in cynomolgus monkeys were 531?ml?h^?1?kg^?1, 5.63?µg?h?ml^?1, 0.96?h and 679?ml?kg^?1, respectively. The AUC_0–t for oral administration of NO-1886 (3?mg?kg^?1) was 4.23?µg?h?ml^?1 and the bioavailability was 75%.

3. M-2 (ethyl 4-[(4-bromo-2-cyanophenyl) carbamoyl] benzylphosphonate) and M-3 (4-[(diethoxy-phosphoryl) methyl)] benzoic acid) were present as metabolites in plasma and urine. In faeces, M-2 was present but M-3 was not.

4. The major metabolite of NO-1886 in liver S9 or microsomes was M-2 in the presence of NADPH. On the other hand, M-3 was formed in the absence of NADPH in liver S9 or microsomes and its formation was inhibited by bis-(?p-nitrophenyl) phosphate (BNPP) in liver S9, suggesting that the formation of M-3 was catalysed by carboxylesterase.

5. The findings suggest that the main metabolic pathway of NO-1886 in cynomolgus monkeys is the O-deethylation of NO-1886 to M-2, as in rats and humans, and that the hydrolysis of the amide bond is a minor metabolic pathway.