Pharmacokinetics of the anticoagulant 14C-DX-9065a in the healthy male volunteer after a single intravenous dose.

1. The plasma pharmacokinetics, excretion and metabolism of DX-9065a were studied in the healthy male Caucasian volunteer after a single intravenous dose of 10 mg 14C-labelled DX-9065a. 2.

Pharmacokinetics and safety of ascending single doses of DZ-2640, a new oral carbapenem antibiotic, administered to healthy Japanese subjects.

DZ-2640 is the ester-type oral carbapenem prodrug of an active parent compound, DU-6681. The pharmacokinetics and safety of DU-6681 were investigated in six studies after oral administration of a single dose of DZ-2640 to healthy male Japanese volunteers at doses of 25, 50, 100, 200, and 400 mg (as the equivalents of DU-6681) in the fasted state. The same volunteers received the drug at a dose of 100 mg in the fasted and fed states to examine the effect of food intake on the bioavailability of DZ-2640.

Pharmacokinetics of CPT-11 in rhesus monkeys.

Purpose: To examine the pharmacokinetic relationships between humans and monkeys, we studied the disposition of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), in rhesus monkeys.

Methods: CPT-11 was administered to a total of six monkeys at doses of 3, 7, 15 and 25 mg/kg by intravenous infusion for 10 min and plasma concentrations and pharmacokinetic parameters of CPT-11 determined.

Results: Maximum plasma concentrations at 25 mg/kg reached around 10000 ng/ml, and dropped to 500 ng/ml in 8 h.

Metabolic disposition of pantoprazole, a proton pump inhibitor, in relation to S-mephenytoin 4'-hydroxylation phenotype and genotype.

Objectives: To assess the possible relationship between the metabolic disposition of pantoprazole and genetically determined S-mephenytoin 4'-hydroxylation phenotype and genotype.

Methods: The pharmacokinetic disposition of pantoprazole was investigated in 14 Japanese male volunteers (seven extensive and seven poor metabolizers of S-mephenytoin). All subjects received a single 40 mg oral dose of pantoprazole as the enteric-coated formulation.

Effects of proton pump inhibitors on thyroid hormone metabolism in rats: a comparison of UDP-glucuronyltransferase induction.

The effects of proton pump inhibitors on thyroid hormone metabolism in rats were examined. Pantoprazole, omeprazole, and lansoprazole were administered repeatedly to female SD rats at doses of 5, 50, and 300 mg/kg/day for 1 week, and changes in UDP-glucuronyltransferase activities were examined. Increases in o-aminophenol UDP-glucuronyltransferase activity, which was measured as that responsible for the glucuronidation of thyroxine, were evident following 7-day high-dose administration of all the proton pump inhibitors tested.

Effects of pantoprazole on xenobiotic metabolizing enzymes in rat liver microsomes: a comparison with other proton pump inhibitors.

The effects of pantoprazole on xenobiotic metabolizing enzymes in rat liver microsomes were examined. Groups of female Sprague-Dawley rats were orally administered pantoprazole and other proton pump inhibitors, omeprazole and lansoprazole, at 5, 50, or 300 mg/kg/day for 7 days, followed by assays to detect changes in the levels of liver microsomal protein, cytochrome P450, cytochrome b5, NADPH cytochrome c reductase, and drug metabolizing enzyme activities. Increases in total cytochrome P450 contents were evident after a 7-day high-dose administration of all the proton pump inhibitors tested, and the increase by treatment with pantoprazole was less than that with lansoprazole.

Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats.

Irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11), is a potent anticancer drug that is increasingly used in chemotherapy. A frequent limiting side effect involves gastrointestinal toxicity (diarrhea), which is thought to be related to the biliary excretion of CPT-11 and its metabolites. Accordingly, the biliary excretion mechanisms for both the lactone and carboxylate forms of CPT-11 and its metabolites, SN-38 and its glucuronide (SN38-Glu), were investigated using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR), with the latter being mutant rats with a genetic deficiency of the canalicular multispecific organic anion transporter.

Differential stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor in extensive and poor metabolizers of pantoprazole--a preliminary study.

Pantoprazole (PAN) is a proton pump inhibitor that is administered as a racemic mixture. The pharmacokinetics of PAN enantiomers were investigated in extensive metabolizers (EMs) and apparent poor metabolizers (PMs) of PAN who received a single, 40, 60, or 80 mg oral dose of racemic PAN as enteric-coated formulation. In the EMs, the serum concentrations of (-)-PAN were slightly higher than those of (+)-PAN at each dose level.

Pharmacokinetics and tolerance of pantoprazole, a proton pump inhibitor after single and multiple oral doses in healthy Japanese volunteers.

The pharmacokinetics and tolerance of pantoprazole were investigated after single (20, 40, 80, and 120 mg) and multiple (80 mg once a day for 7 days) oral administration as enteric-coated tablet formulation to healthy male Japanese volunteers. Pantoprazole was well tolerated with no serious adverse events at all doses. Pantoprazole was rapidly absorbed in the fasted state.

Identification of major biliary and urinary metabolites of ecabapide in rats.

1. The structures of major biliary and urinary metabolites of ecabapide in rat were identified by comparison with authentic standards using lc-ms and 1H-nmr spectrometry. 2.

Nefiracetam hydroxylation by rat liver microsomes and expressed human cytochrome P450s.

1. The metabolism of nefiracetam, a novel cognition-enhancer, by rat liver microsomes has been studied. 2.

Simple and selective assay of 4-hydroxymephenytoin in human urine using solid-phase extraction and high-performance liquid chromatography with electrochemical detection and its preliminary application to phenotyping test.

A simple and selective HPLC method for the determination of 4-hydroxymephenytoin (4-OH-M) in human urine, using a controlled potential coulometric detector equipped with a dual working electrode cell of fully porous graphite, has been developed. After acid hydrolysis of urine, 4-OH-M and the internal standard (I.S.

Placental transfer and milk secretion of gadodiamide injection in rats.

The disposition of gadodiamide (CAS 122795-43-1) injection (Omniscan), a nonionic paramagnetic contrast-enhancing medium developed for magnetic resonance imaging, was characterized in the pregnant and lactating rat. After a single intravenous dose of 0.3 mmol/kg 14C-labeled gadodiamide to rats on day 18 of gestation, the maximum levels of radioactivity in the fetus were attained at 5 min, and were approximately 170 times lower than those in the maternal plasma.

Pharmacokinetics and stability of caldiamide sodium in rats.

Gadodiamide (CAS 122795-43-1) injection (Omniscan) is a formulation composed of gadolinium (III) complexed with diethylenetriaminepentaacetic acid bis-methylamide (Gd DTPA-BMA) and the sodium calcium complex of the same ligand, known as caldiamide sodium (CAS 122760-91-2, NaCa DTPA-BMA), in a molar ratio of 20:1. Following intravenous dosing of NaCa DTPA-BMA (0.015 mmol/kg) in a 14C-labeled form, plasma concentrations of the drug declined rapidly with an elimination half-live of 0.

Isolation and identification of seven metabolites of a water-soluble platelet aggregation inhibitor in rat urine.

1. Seven metabolites of 7-piperidino-1,2,3,4,5-tetrahydroimidazo[2,1- b]quinazolin-2-one dihydrochloride monohydrate (DN-9693) were isolated from rat urine by extraction with Amberlite XAD-2 and purification by silica gel and Sephadex LH-20 open-column chromatography and preparative high-performance liquid chromatography (hplc). The structure assignment of the metabolites was performed by field desorption mass spectrometry and 200-MHz Fourier transform nmr spectroscopic analysis and comparison with authentic standards when available.

Pharmacokinetics and tolerance of a new fluoroquinolone antimicrobial drug after single oral doses in healthy volunteers.

1. The pharmacokinetics and tolerance of DV-7751a were investigated in healthy male Caucasian volunteers after single oral doses (100, 200, 400 and 800 mg). 2.

Biliary metabolites of semotiadil fumarate in the rat.

After oral administration of 14C-semotiadil fumarate to rat, 81.3% of the dosed radioactivity was excreted into the bile. Five major biliary metabolites were detected and characterized as phenolic O-glucuronides by FAB mass spectrometry and 1H-nmr spectrometry.

Pharmacokinetics of SN-38 [(+)-(4S)-4,11-diethyl-4,9-dihydroxy-1H- pyrano[3',4':6,7]-indolizino[1,2-b]quinoline-3,14(4H,12H)-dione], an active metabolite of irinotecan, after a single intravenous dosing of 14C-SN-38 to rats.

Irinotecan (CPT-11) is a camptothecin derivative used for the treatment of cancer. It is a prodrug that is metabolized to its active form, SN-38 [(+)-(4S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]- indolizino[1,2-b]quinoline-3,14(4H,12H)-dione]. To clarify the pharmacokinetic difference between CPT-11 and SN-38, the plasma levels, tissue distribution and excretion of SN-38 were investigated after dosing rats with 14C-labeled SN-38.

In vitro metabolism of nefiracetam by liver microsomes from rats, dogs and monkeys.

The in vitro metabolism of nefiracetam (CAS 77191-36-7, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, NEF, DM-9384), a novel cognition enhancer, has been investigated using liver microsomes from rats, dogs and monkeys. Microsomal metabolism of NEF showed qualitatively a similar profile in three species tested. Six metabolites were generated from incubation of NEF with liver microsomes.

Metabolism of irinotecan to SN-38 in a tissue-isolated tumor model.

The objective of this study is to investigate the metabolism of the antitumor drug, irinotecan (CPT-11), to its active metabolite, SN-38, in tumor tissue. Using Walker 256 carcinoma, we prepared a tissue-isolated tumor model: tumor preparation was continuously perfused with Krebs-Henseleit bicarbonate buffer containing 4% bovine serum albumin (BSA) and CPT-11 (10 micrograms/ml), and the concentration of SN-38 in the perfusate was monitored using HPLC. The concentration of SN-38 in the perfusate was gradually increased to a level of 9.

Modulation of subcellular particles of the rat small intestine and liver by ebselen.

Reactions between ebselen and subcellular particles of rat liver were investigated by monitoring the activity of mitochondrial glutamate dehydrogenase and microsomal glucose 6-phosphate dehydrogenase. Rat small intestine lactate dehydrogenase was purified and was also used in the reaction between cytosolic protein and ebselen. Glutamate dehydrogenase in intact rat liver mitochondria was completely resistant to ebselen, but the enzyme was significantly inactivated in broken mitochondria mediated by Triton X-100, reflecting the fact that ebselen was not transported through the mitochondrial membrane into the matrix.

Determination of a new fluoroquinolone antimicrobial agent, (S)-10-[(S)-(8-amino-6-azaspiro d3,4]octan-6-yl)]-9-fluoro-2, 3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6- carboxylic acid hemihydrate, DV-7751a, in human serum and urine using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

A high-performance liquid chromatographic method for the determination of a new fluoroquinolone antimicrobial agent, (S)-10-[(S)-(8-amino-6-azaspiro[3,4]octan-6-yl)]-9-fluoro-2,3- dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate (DV-7751a, I) in human serum and urine has been developed. Compound I and the internal standard were extracted from serum and urine by means of Bond Elut C8 LRC column. The extracts were chromatographed on a reversed-phase Inertsil ODS-2 column using tetrahydrofuran-50 mM KH2PO4 (pH2)-1 M ammonium acetate (19:81:1, v/v) as the mobile phase at a flow-rate of 1.

Pharmacological correlation between total drug concentration and lactones of CPT-11 and SN-38 in patients treated with CPT-11.

The pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were examined to establish the pharmacokinetic variability of the active lactones of CPT-11 and SN-38 in comparison with that of the total (lactone and carboxylates) plasma CPT-11 and SN-38. Twelve patients with malignancies were entered in the study. All received 100 mg/m2 of CPT-11 by intravenous drip infusion over 90 min.

A pharmacokinetic and pharmacodynamic analysis of CPT-11 and its active metabolite SN-38.

In the present study, an attempt was made to determine the precise pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). The relationship between pharmacokinetic parameters and pharmacodynamic effects was also investigated to elucidate the cause of interpatient variation in side effects. Thirty-six patients entered the study.