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Clearance Decreased (clearance + decreased)
Selected AbstractsNo pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2009An Thyssen Abstract Objective The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed. Methods Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6,mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200,mg twice daily. Serial blood and urine samples were collected for PK and plasma protein binding of paliperidone and its enantiomers. The 90% confidence interval (CI) of ratios with/without trimethoprim for PK parameters of paliperidone and its enantiomers calculated. Results Creatinine clearance decreased from 119 to 102,mL,min,1 with trimethoprim. Addition of trimethoprim increased unbound fraction of paliperidone by 16%, renal clearance by 13%, AUC, by 9%, and t½ by 19%. The 90% CIs for ratios with/without trimethoprim were within the 80,125% range for Cmax, AUClast, and renal clearance. For AUC,, 90% CI was 79.37,101.51, marginally below the lower bound of the acceptance range. Paliperidone did not affect steady-state plasma concentrations of trimethoprim. Conclusions No clinically important drug interactions are expected when paliperidone ER is administered with organic cation transport inhibitors. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effects of length of cut and mechanical processing on utilization of corn silage harvested at the black line stage of maturity by lactating dairy cowsANIMAL SCIENCE JOURNAL, Issue 2 2010Satoshi HARA ABSTRACT The effects of length of cut and mechanical processing on corn silage utilization by dairy cows were evaluated. Corn silage treatments were harvested at the black line stage of maturity and chopped at a theoretical length (TLC) of 9.5 mm without processing (Control) or at a TLC of 19 mm with processing at roller clearances of 1, 3, or 5 mm. Eight multiparous Holstein cows were assigned in a replicated 4 × 4 Latin square design with 21-day periods. Corn silage treatments were fed in diets containing 78.3% corn silage and 21.7% soybean meal (DM basis). Treatments had no significant effects on DMI, milk and 4% FCM production. The efficiency of converting DMI to FCM tended to be greater with processing at a roller clearance of 1 and 3 mm than at other clearances. Apparent total tract digestibility of starch tended to be lowest for cows fed control silage, and increased as roller clearance decreased. Ruminal ammonia concentrations in cows fed control silage were numerically higher than in cows fed proccesed silages. These results suggest that when corn silage is harvested at the black line of maturity, roller clearance should be 3 mm or less with a TLC of 19 mm. [source] Pharmacokinetic modelling of blood,brain barrier transport of escitalopram in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2007Christoffer Bundgaard Abstract This study examined the pharmacokinetics and distribution of escitalopram in the brain extracellular fluid in rats by the concurrent use of intracerebral microdialysis and serial blood sampling. Following three constant intravenous infusions, drug concentrations in the hippocampus and plasma were monitored for 6 h. To estimate the integrated pharmacokinetics and intercompartmental transport parameters, including blood,brain barrier (BBB) transport over the entire dose range, unbound brain and plasma escitalopram concentration data from all doses were simultaneously analysed using compartmental modelling. The pharmacokinetic analysis revealed that systemic clearance decreased as a function of dose, which was incorporated in the integrated model. Escitalopram was rapidly and extensively transported across the BBB and distributed into the brain extracellular fluid. The modelling resulted in an estimated influx clearance into the brain of 535 µl/min/g brain, resulting in an unbound brain-to-plasma AUC ratio of 0.8 independent of escitalopram dose. The model may be applied for preclinical evaluations or predictions of escitalopram concentration-time courses in plasma as well as at the target site in the CNS for various dosing scenarios. In addition, this modelling approach may also be valuable for studying BBB transport characteristics for other psychotropic agents. Copyright © 2007 John Wiley & Sons, Ltd. [source] Dose-dependent pharmacokinetics of 1-(2-Deoxy- , - D - ribofuranosyl)-2,4-difluoro-5-iodobenzene: A potential mimic of 5-iodo-2,-deoxyuridineBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2003Panteha Khalili Abstract The dose-range pharmacokinetics of l-(2-deoxy- , - D -ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR), a C -aryl nucleoside mimic of IUdR, were studied in male Sprague-Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from ,32 ml/min/kg at a dose of 15 mg/kg, to ,19 ml/min/kg when dosed at 54 mg/kg, and the elimination half-life increased from 8.4 min to 21.5 min, for the respective doses. While the dose-normalized area under the concentration-time curve (AUCnorm) remained practically unchanged (0.132 kg min ml,1) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% (,0.19 kg min ml,1) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose-dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half-life increased from 24.5 min to 176 min, while blood clearance was reduced from ,37 ml/min/kg to ,17 ml/min/kg. The urinary recoveries of unchanged 5-IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5-IDFPdR (as percent of the dose) was, however, decreased with increasing doses. The overall kinetic profile of 5-IDFPdR based on these data is suggestive of dose-dependent pharmacokinetics. Decreased elimination of 5-IDFPdR with increasing dose, as supported by longer elimination half-lives at higher doses, is one likely mechanism contributing to the dose-dependent behaviour of this compound. Saturable non-renal metabolism might explain the reduced total body clearance of 5-IDFPdR at higher doses, despite the unchanged or increased urinary clearance. For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5-IDFPdR, which may be of therapeutic relevance, warrants extended dose-range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens. Copyright © 2003 John Wiley & Sons, Ltd. [source] Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administrationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2002Alfred E. Corey Aims To assess the influence of severe renal impairment on azimilide pharmacokinetics. Methods A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22,28 and 10 days, respectively. Results Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h,1 kg,1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h,1 kg,1, 95% confidence interval on the ratio 0.67, 1.36) was observed. Conclusions Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment. [source] | ||||||||||