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. At the end of a 1 h infusion, the mean plasma concentration of total radioactivity was 380 ng ml(-1) (equivalent to unchanged DX-9065). Thereafter, it decreased in a bi-exponential manner and was below the detection limit by 48 h after dosing. The half-life for the distribution phase was 6.93 h. 3. The total radioactivity recovered in urine and faeces by 336 h post-dose was 83.8% of the administered dose, with excretion ongoing at the end of the 14-day collection. The major route of excretion was via urine, accounting for a mean of 77.6% of the administered radioactivity. The urinary excretion profile was biphasic, consisting of rapid (0-24 h) and slow (24-336 h) phases. A large renal clearance suggested that renal tubular secretion might contribute to the excretion of DX-9065 via urine. 4. No metabolite peaks in the radio-HPLC chromatograms of urine samples were detected, indicating that biotransformation of DX-9065 does not play a significant role in the elimination of DX-9065 in man.

Human xenobiotic metabolizing esterases in liver and blood.

Esterases in human liver microsomes hydrolysed fluazifop-butyl (Vmax 9.8 +/- 1.6 mumol/min/g tissue), paraoxon (Vmax 47.4 +/- 7.5 nmol/min/g tissue) and phenylacetate (Vmax 57 +/- 8 mumol/min/g tissue), whereas esterases found in the human liver cytosol hydrolysed fluazifop-butyl (Vmax 10.0 +/- 0.5 mumol/min/g tissue) and phenylacetate (Vmax 37 +/- 2.9 mumol/min/g tissue) but not paraoxon. Human plasma esterase hydrolysed fluazifop-butyl (Vmax 0.09 +/- 0.006 mumol/min/mL), paraoxon (Vmax 210 +/- 14 nmol/min/mL) and phenylacetate (Vmax 250 +/- 17 mumol/min/mL). Inhibitory studies using paraoxon, bis-nitrophenol phosphate and mercuric chloride indicated fluazifop-butyl hydrolysis involved carboxylesterase in liver microsomes and cytosol, and cholinesterase and carboxylesterase in plasma. Phenylacetate hydrolysis involved arylesterase in plasma, both arylesterase and carboxylesterase in liver microsomes and carboxylesterase in liver cytosol. Plasma hydrolysis is less important and overall esterase activity is lower in humans than in the rat which is therefore a poor model.

Peripheral esterases in the rat: effects of classical inducers.

Liver microsomal paraoxonase, aryl esterase and fluazifop butyl esterase (carboxylesterase) were induced by pretreatment of rat with phenobarbitone but not by beta-naphthoflavone or clofibric acid. In the extrahepatic tissues lung cytosolicfluazifop butyl and phenylacetate esterase were induced.

Nature and role of xenobiotic metabolizing esterases in rat liver, lung, skin and blood.

In the present study, the distribution and nature of esterases in the rat which hydrolysed fluazifop-butyl, carbaryl, paraoxon and phenylacetate were investigated. Vmax and Km values for the hydrolysis reactions were determined. Fluazifop-butyl was hydrolysed to fluazifop by rat liver (Vmax mumol/min/g microsomes 6.2 +/- 0.4; cytosol 6.84 +/- 0.85), lung (Vmax microsomes 0.38 +/- 0.1; cytosol 1.5 +/- 0.32) and skin (Vmax microsomes 0.02 +/- 0.0015; cytosol 0.4 +/- 0.06) and by plasma (Vmax mumol/min/mL 5.8 +/- 0.48) and red blood cells (Vmax 0.03 +/- 0.015). Significant inhibition by paraoxon and bismitrophenol phosphate indicated the involvement of carboxylesterases. Carbaryl was hydrolysed by liver, lung and skin at a lower rate by microsomal fractions (Vmax nmol/min/g 2.1 +/- 0.25, 1.6 +/- 0.25, 0.2 +/- 0.035, respectively) compared to cytosolic fractions (Vmax 6.7 +/- 0.75, 1.4 +/- 0.36, 0.5 +/- 0.12) and plasma (Vmax nmol/min/mL 3.0 +/- 0.25). Hydrolysis involved carboxylesterases. Paraoxon was hydrolysed by paraoxonases/arylesterases only in the plasma (Vmax nmol/min/mL 246 +/- 12) and microsomal fractions from liver (Vmax 330 nmol/min/g +/- 25) and lung (Vmax 2 +/- 0.25). Phenylacetate was hydrolysed by both microsomal and cytosolic fractions from all tissues studied. Hydrolysis involved arylesterases in the microsomes and carboxylesterases in the cytosol. Extrahepatic hydrolysis may be important following some routes of exposure to xenobiotic esters.