Lack of pharmacokinetic and pharmacodynamic interactions of roflumilast with (R, S)-warfarin in healthy adult subjects.

UNLABELLED: Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved for the treatment of severe COPD. The pharmacological effect is mediated mainly by its active metabolite roflumilast N-oxide. OBJECTIVE: This doubleblind, 2-period cross-over study was conducted to investigate the potential effects of concomitant roflumilast on pharmacokinetics and pharmacodynamics of warfarin and vice versa. MATERIALS AND METHODS: A total of 24 healthy adults was enrolled into the study. Once-daily oral doses of roflumilast (500 µg) or placebo were given for 12 days, with subjects receiving both treatments one after the other; single oral doses of (R,S)-warfarin (25 mg) were administered on Day -14 and Day 8 of both periods. Warfarin enantiomer concentrations, prothrombin time (PT), and clotting factor activity (Factor VII, only) as well as concentrations of roflumilast and roflumilast N-oxide were measured in plasma. RESULTS: There was no clinically relevant pharmacokinetic or pharmacodynamic interaction between warfarin and roflumilast. Exposure over 120 h (area under the curve, AUC0-120) with "Test" (warfarin plus roflumilast) and "Reference" (warfarin plus placebo) treatment for Factor VII (geometric mean ratio 102.1% (90% confidence interval: 99.7 - 104.7%)) and excess AUC0-120 for PT (99.3% (92.3 - 106.9%)) were unchanged. CONCLUSIONS: Pharmacokinetic parameters including maximum plasma concentration (Cmax) and AUC0-∞ of (R)-, (S)-warfarin, roflumilast, and roflumilast N-oxide were unaffected by co-administration.

Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide.

OBJECTIVE: To investigate the effects of steady state erythromycin on the pharmacokinetics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide in healthy subjects. Both roflumilast and roflumilast N-oxide have similar intrinsic PDE4 inhibitory activity; the total PDE4 inhibition (tPDE4i) in humans is likely due to the combined effect of roflumilast and roflumilast N-oxide. METHODS: Subjects (n = 16) received single oral roflumilast 500 microg once daily (Days 1 and 15), and repeated oral erythromycin 500 mg three times daily (Days 9 - 21). Percent ratios of Test/Reference (Reference: roflumilast alone; Test: roflumilast and steady-state erythromycin) were calculated for the geometric means and their 90% confidence intervals for systemic exposure (AUC), maximum concentration (Cmax) (roflumilast and roflumilast N-oxide), and apparent clearance of roflumilast. RESULTS: After co-administration of erythromycin and roflumilast, the mean AUC and Cmax of roflumilast increased by 70% and 40%, respectively. The mean apparent clearance of roflumilast decreased from 8.2 l/h (Reference) to 4.8 l/h (Test). Steady-state erythromycin did not alter the mean AUC of roflumilast N-oxide, however, the mean Cmax decreased by 34%. The AUCroflumilast N-oxide/AUCroflumilast ratio decreased from 10.6 (Reference) to 6.4 (Test). Co-administration of erythromycin and roflumilast did not influence the integrated total exposure to roflumilast and roflumilast N-oxide, i.e. mean tPDE4i. No clinically relevant adverse events were observed during the study. CONCLUSIONS: Co-administration of erythromycin (a moderate CYP3A4 inhibitor) and roflumilast does not require dose adjustment of roflumilast.

Absorption, distribution, metabolism and excretion of [14C]levocetirizine, the R enantiomer of cetirizine, in healthy volunteers.

The main goal of the present study was to investigate the absorption and disposition of levocetirizine dihydrochloride, the R enantiomer of cetirizine dihydrochloride, following a single oral administration (5 mg) of the 14C-labelled compound in healthy volunteers. Configurational stability was also investigated. Levocetirizine was rapidly and extensively absorbed: 85.4% and 12.9% of the radioactive dose were recovered 168 h post-dose in urine and faeces, respectively. Levocetirizine and/or its metabolites were not, or only very poorly, associated with blood cells, as the blood-to-plasma ratio was 0.51 to 0.68. The mean apparent volume of distribution (Vz/F) was 26.9 1 (0.3 l/kg) indicating that the distribution of levocetirizine is restrictive. The protein binding of radiolabelled levocetirizine was 96.1% l h after administration. In vitro, at concentrations ranging from 0.2 microg/ml to 1 microg/ml, the protein binding was 94.8% to 95.0%. Levocetirizine is very poorly metabolised. The cumulative 48-h excretion as parent compound accounted for 85.8% of the oral dose, equivalent to 95% of the total radioactivity excreted at this time. At least 13 minor metabolites were detected in urine and represented 2.4% of the dose at 48 h. The metabolic pathways involved in levocetirizine metabolism are oxidation (hydroxylation, O-dealkylation, N-oxidation and N-dealkylation), glucuroconjugation, taurine conjugation and glutathione conjugation with formation of the mercapturic acids. There was no evidence of chiral inversion of levocetirizine in humans. This result is consistent with that obtained in preclinical studies.

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.

Ticarcillin-induced neutropenia corroborated by in vitro CFU-C toxicity.

A patient developed a drug rash and neutropenia while receiving tobramycin, ticarcillin and flucloxacillin intravenously for osteomyelitis. Incorporation of these antibiotics into in vitro cultures of bone marrow granulocyte macrophage precursors (CFU-C) showed no inhibition of the patient's marrow or normal marrow by tobramycin. The patient's marrow was more sensitive to ticarcillin than were control cultures, and all cultures incorporating flucloxacillin failed to show growth of CFU-C. Drugs of the penicillin group appear to be responsible for the patient's neutropenia.