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Dose Linearity (dose + linearity)
Selected AbstractsPharmacokinetics of pyrrole-imidazole polyamides after intravenous administration in ratBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2009Akiko Fukasawa Abstract The pharmacokinetics of pyrrole (Py)-imidazole (Im) polyamides was studied in rats after the intravenous administration of these compounds. Py-Im polyamide (A) was composed of Ac-ImPyPy-ImPyPy-,-Dp (,: ,-alanine, Dp: N,N -dimethylaminopropylamide). Py-Im polyamide (B) was composed of Ac-PyIm-,-ImIm-PyPy-,-PyPy-,-Dp. Py-Im polyamide (C) was composed of Ac-PyPy-,-PyImPy-PyPyPy-,-ImPy-,-Dp. The molecular weight of Py-Im polyamide (A) was 1035.12, that of Py-Im polyamide (B) was 1422.51 and that of Py-Im polyamide (C) was 1665.78. After the intravenous injection of Py-Im polyamide (A) at 1.3, 2.0, 7.5 and 15.0,mg/kg, Py-Im polyamides (B) and (C) at 1.0, 2.0, 3.0 and 5.0,mg/kg, the average systemic clearance and the volume of distribution at the steady state obtained by a non-compartmental method were in the ranges of 4.6,6.4,ml/min/kg and 244,412,ml/kg, 8.9,10.3,ml/min/kg and 1990,4567,ml/kg, and 7.3,11.9,ml/min/kg and 407,667,ml/kg, respectively. Dose linearity of Py-Im polyamides was observed. The plasma concentration-time profiles after the intravenous administration of Py-Im polyamides (A) and (B) were fitted well by a two-compartment model. Py-Im polyamide (C) was observed at high concentrations in the lungs. The plasma concentration-time profiles after the intravenous administration of Py-Im polyamide (C) were described using a catenary two-compartment model. This model is useful for describing the time course after the administration of high-molecular-weight Py-Im polyamides. Copyright © 2009 John Wiley & Sons, Ltd. [source] Pharmacological and pharmacokinetic evaluation of celecoxib prodrugs in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2002Rao N.V.S. Mamidi Abstract This study demonstrates the utility of an in vitro , in vivo correlative approach in the selection and optimization of a prodrug candidate of celecoxib (CBX), a COX2 inhibitor. As an initial screening step, a comparative single oral dose pharmacokinetic study was conducted in rats for CBX and its three aliphatic acyl water-soluble prodrugs viz., CBX-acetyl (CBX-AC), CBX-propionyl (CBX-PR) and CBX-butyryl (CBX-BU) at high equimolar dose, 100 mg/kg. Only CBX-BU and CBX-PR converted rapidly to CBX and yielded approximately five-fold greater systemic exposure of CBX than CBX alone or CBX-AC. Rank order of systemic exposure of prodrugs in its intact form was CBX-AC >CBX-PR >CBX-BU. Further in vitro hydrolysis studies of CBX prodrugs in intestinal mucosal suspensions and liver homogenates indicated that CBX-BU is rapidly and completely converted to CBX, whereas CBX-PR and CBX-AC require longer incubation period for complete conversion to CBX. There was a very good correlation of the in vitro and in vivo data supporting CBX-BU as the prodrug of choice. Further in vitro pharmacological studies showed that COX2 selective inhibition is improved for CBX-BU as compared to CBX-AC and CBX-PR. Dose proportionality in pharmacokinetic studies of CBX-BU and CBX at equimolar oral doses confirmed that relative oral bioavailability of CBX was improved following CBX-BU administration and there was linearity in pharmacokinetics of CBX over a wide dose range (10,100 mg/kg), whereas CBX in its conventional form showed poor bioavailability and lack of dose linearity in pharmacokinetics. The oral bioavailability of CBX from CBX-BU was dose independent and was in the range 78,96%. At a 50% reduced molar dose, CBX-BU showed an equivalent efficacy to that of CBX in the in vivo carrageenan model. Based on the study, water-soluble CBX-BU prodrug can be considered for clinical development in view of its potential advantages.Copyright © 2002 John Wiley & Sons, Ltd. [source] Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal womenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006M. Rad Aims Pre-clinical data suggest that the racemic phyto-oestrogen 8-prenylnaringenin (8-PN) may have beneficial effects in postmenopausal women and may become an alternative to classical hormone replacement therapy (HRT) treatment regimes. The aim of this study was to investigate the pharmacokinetics, endocrine effects and tolerability of chemically synthesized 8-PN in postmenopausal women. Methods The study was performed using a randomized, double-blind, placebo-controlled, dose-escalation design with three groups of eight healthy postmenopausal women. In each group six subjects received 8-PN and two subjects placebo. 8-PN was given orally in doses of 50, 250 or 750 mg. Drug concentrations in serum, urine and faeces were measured up to 48 h and follicle-stimulating hormone/luteinizing hormone (LH) concentrations up to 24 h. Results All treatments were well tolerated and associated with a low incidence of (drug unrelated) adverse events. Serum concentrations of free 8-PN showed rapid drug absorption and secondary peaks suggestive of marked enterohepatic recirculation. Independent of the treatment group, approximately 30% of the dose was recovered in excreta as free compound or conjugates over the 48-h observation period. The first Cmax and AUC0,48 h showed dose linearity with ratios of 1 : 4.5 : 13.6 (Cmax) and 1 : 5.2 : 17.1 (AUC). The750- mg dose decreased LH concentrations by 16.7% (95% confidence interval 0.5, 30.2). Conclusion Single oral doses of up to 750 mg 8-PN were well tolerated by postmenopausal women. The pharmacokinetic profile of 8-PN was characterized by rapid and probably complete enteral absorption, high metabolic stability, pronounced enterohepatic recirculation and tight dose linearity. The decrease in LH serum concentrations found after the highest dose demonstrates the ability of 8-PN to exert systemic endocrine effects in postmenopausal women. [source] | ||||||||||