bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distribution of oral nimesulide in female genital tissues
Authors: Pulkkinen Martti O. , Vuento Maarit , Macciocchi Alberto , Monti Tlziana 
Published: October 2006

AbstractNimesulide is a non‐steroidal anti‐inflammatory agent which has proved to be effective in reducing menstrual discomfort in dysmenorrhoeaic women. To determine the concentrations of this drug in the uterus (fundus, cervix), oviduct, and ovaries and to correlate these findings with plasma concentrations, a single oral dose of 100mg nimesulide was administered 1 to 6h before surgery to 12 women undergoing hysterectomy and salpingo‐oophorectomy, mainly for fibroids. Tissue samples were taken, concentration of nimesulide measured by HPLC, and findings compared with plasma concentrations. One patient not undergoing treatment served as control. Nimesulide concentration in the tissues studied was highest 3h after administration, as expected from the drug's pharmacokinetic profile. The highest tissue/plasma ratio (0·5) was also found at that time. Average tissue concentrations at 1, 2, 3, and 6h after drug intake ranged from 0·3 to 1·8μgg−1, and plasma concentrations from 2·6 to 4·1μgml−1. Nimesulide was evenly distributed in the tissues studied.
Distribution kinetics of netilmicin in human blister fluid: Effect of renal impairment
Authors: Lanao J. M. , López A. , Domínguez‐gil A. , Martin J. , Gómez J. R. , Tabernero J. M. 
Published: October 2006

AbstractThe pharmacokinetics of netilmicin in plasma and blister fluid were compared in 10 healthy volunteers with normal renal function and 10 voluntary patients with varying degrees of renal impairment. Netilmicin kinetics in plasma were characterized by an open two‐compartment kinetic model. For the study of the kinetics of the antibiotic in blister fluid a specific kinetic distribution model was employed. In the healthy volunteers the plasma kinetics of netilmicin showed a behaviour similar to that of other aminoglycoside antibiotics, although a high blister/plasma partition coefficient was obtained, with a mean value of 4·27·1·65. The transfer of netilmicin in blister fluid governed by the constants Klb/Vb and Kbl had mean values of 0·19·0·09h−1 I−1 and 0·25·0·10h−1, respectively. In the patients with renal impairment plasma and blister fluid antibiotic levels showed a progressive accumulation. In these patients the affinity of netilmicin for blister fluid was significantly altered. The blister/plasma partition coefficient in this group of patients had a mean value of 2·65·1·33; the decrease being statistically significant (p=0·023) with respect to the value obtained in the healthy volunteers. Similarly, the exit constant of netilmicin from blister fluid (Kbl) showed a statistically significant increase (p=0·035) in the patients with renal impairment. The findings point to a loss of affinity of netilmicin for blister fluid as a result of renal impairment. Linear and logarithmic relationships were established between some pharmacokinetic parameters and creatinine clearance. Dosage schedules are proposed for netilmicin in patients with renal impairment.
Effects of ethanol and Δ9‐tetrahydrocannabinol on phencyclidine disposition in dogs
Authors: Godley Paul J. , Moore Emory S. , Woodworth James R. , Fineg Jerry 
Published: October 2006

AbstractA three‐way crossover study was performed to determine the influence of Δ9‐tetrahydro‐cannabinol (THC) and ethanol (EtOH) separately upon phencyclidine (PCP) disposition in dogs. Seven dogs were given three single dose treatments: 1·5mg PCP kg−1 i.v., 1·5 mg PCP kg−1 i.v. with 0·4mgkg−1 THC i.v., and 1·5 mg PCP kg−1 i.v. with 1·25g EtOH kg−1 i.v. PCP was measured in plasma samples collected for 24h after administration of each treatment, with several pharmacokinetic parameters calculated from the plasma concentration vs time data. The PCP serum Cls values were significantly lower when administered with THC than when administered alone, with no significant change in Vβ or t1/2. EtOH did not induce significant changes in any PCP pharmacokinetic parameter, although mean Cls and Vβ were increased. These results confirm the observed THC inhibition of PCP metabolism, and suggest that the enhanced pharmacologic action of PCP by THC may result from higher serum PCP concentrations. These results further suggest that enhanced PCP actions by acute EtOH administration may result from increased PCP distribution to the CNS.
Characterization of ethiofos absorption in the rat small intestine
Authors: Geary Richard S. , Swynnerton Nollie F. , Timmons Scott F. , Mangold Donald J. 
Published: October 2006

AbstractThe absorption characteristics of ethiofos were studied using the rat in situ intestine circulating perfusion technique. Slow absorption kinetics were observed for ethiofos with varying rates of absorption and metabolism/degradation in situ as a function of buffer and absorption enhancers. In most cases less than 10 per cent of the radiolabeled compound is lost from the circulating perfusate in 90 min. In addition, over the same time period greater than 40 per cent of the intact parent compound was lost by degradation. Much of the difference can be accounted for in the formation of the free thiol metabolite, WR‐1065, suggesting ester hydrolysis or metabolic activity. Good stability was observed in all perfusate systems ex vivo indicating that the degradation occurs in situ. The disodium salt of ethylenediaminetetraacetic acid (EDTA) was shown to be an effective absorption enhancer of ethiofos. The enhancement of intestinal absorption by EDTA was dose‐dependent resulting in a 20‐fold increase in blood levels of ethiofos in the portal blood. Follow‐up studies in the rhesus monkey confirm this observation. Salicylate and dimethylsulfoxide (DMSO) also resulted in absorption enhancement although to a lesser degree than that seen after EDTA treatment. Addition of several alkaline phosphatase inhibitors did not significantly improve absorption of ethiofos in the rat small intestine. Proposed mechanism(s) for intestinal absorption and absorption enhancement of ethiofos are discussed.
Characterization of WR‐1065 absorption in the rat small intestine
Authors: Geary R. S. , Swynnerton N. F. , Timmons S. F. , Mangold D. J. 
Published: October 2006

AbstractA circulating in situ rat small intestine absorption model was used to study the lumenal metabolism and absorption of [14]WR‐1065. WR‐1065 was found to be more tissue reactive and toxic than its phosphorylated form, ethiofos, at equimolar perfusate concentrations. The disappearance profiles of the radiolabeled drug and free WR‐1065 indicate that WR‐1065 is extensively metabolized in the intestinal lumen prior to absorption. Coadministration of disodium ethylenediaminetetraacetic acid enhances the absorption of the free thiol although not to the same extent as seen with ethiofos. Perfusion of WR‐1065 in citrate buffer decreased lumenal degradation of the drug but resulted in decreased absorption. The total material converted to WR‐1065 portal blood profiles following ethiofos and WR‐1065 perfusion were altered possibly due to distribution and metabolism differences. This study coupled with earlier work completed on ethiofos have increased our understanding of the significant barriers to absorption observed following oral administration of these compounds.
Apparent stereoselectivity in propafenone uptake by human and rat erythrocytes
Authors: Mehvar Reza 
Published: October 2006

AbstractThe distribution of propafenone (PPF) enantiomers between the plasma and red blood cells (RBCs) was investigated using human and rat blood. In separate experiments, effects of incubation time (15–60 min), blood concentration (100–5000 ng ml−1), and plasma proteins on the RBC uptake of the enantiomers were studied. In both humans and rats, the distribution of propafenone enantiomers into RBCs was rapid, extensive, and stereoselective. However, the extent of RBC uptake and the direction of stereoselectivity were different in these two species. In humans, preferential distribution of (–)‐PPF into RBCs resulted in lower plasma concentrations for this enantiomer, whereas in rat plasma, (–)‐PPF was the dominant enantiomer. When the plasma was replaced with buffer, the stereoselectivity in the RBC uptake of the enantiomers was abolished. This suggested that stereoselective protein binding may be responsible for this phenomenon. A direct measurement of the extent of binding of PPF enantiomers to rat and human plasma proteins further confirmed this. Moreover, the distribution of the enantiomers in RBCs was not affected by low temperatures or addition of ouabain, suggesting passive diffusion as the underlying mechanism. These results suggest that stereoselective red blood cell uptake may be responsible, at least in part, for the differences in the plasma pharmacokinetics of PPF enantiomers observed after the drug administration to humans and rats.
Stability of diltiazem in different biological fluids
Authors: McLean Angus M. , Cefali Eugenio A. , Roden Jennifer S. , Gonzalez Mario A. , Bialer Meir 
Published: October 2006

AbstractThe hydrolysis of diltiazem in biological fluids: whole blood, plasma, and gastric fluid was investigated under conditions considered close to the physiological situation. The most significant rate of hydrolytic degradation was found in whole blood (half‐life of 27h), followed by plasma (half‐life of 88h), while the least significant degradation rate was observed in gastric fluid (half‐life 153h). The kinetic profiles of diltiazem hydrolysis indicate that hydrolytic degradation in the biological fluids makes a minimal contribution to the clearance and disposition of the drug.
Kinetics of acetaminophen after single‐ and multiple‐dose oral administration as a gradient matrix system to healthy male subjects
Authors: Van Bomml Elvira M. G. , Raghoebar Maikel , Tukker Josef J. 
Published: October 2006

AbstractThe in vivo characteristics of two formulations of a recently developed controlled‐release system, the Gradient Matrix System (GMS‐1 and GMS‐2), with acetaminophen as a model drug compound have been determined in healthy volunteers both after separate single‐ and multiple‐dose administration. Values for the mean residence time (MRT) were increased from 5·2 h for an oral solution to 10·2 and 13·3 h for two GMS formulations after single dosing. Peak plasma concentrations were lower for the two GMS formulations after single dosing compared to the oral solution. The bioavailability, relative to the oral solution, was 91 per cent and 84 per cent for the two GMS formulations tested. After multiple dosing of one of the GMS formulations over 5 days, no change in AUC compared to the single dose AUC occurred. Steady state was reached within 2–3 days of twice daily dosing of the GMS formulation. The peak‐trough‐fluctuation (per cent PTF) was 44 per cent. No signs of dose dumping were observed in fasted subjects. A plateau‐like plasma drug concentration profile at steady state was maintained with the GMS formulation.
Comparative bioavailability of two flurbiprofen products: Stereospecific versus conventional approach
Authors: Jamali Fakhreddin , Collins David S. , Berry Brian W. , Molder Susan , Cheung Richard , McColl Kate , Cheung Helen 
Published: October 2006

AbstractIn this randomized, crossover study comparing the bioavailability of a film‐coated (Ansaid) with a sugar‐coated (Froben) 100 mg tablets of racemic flurbiprofen in 23 healthy young men, no significant differences were found for Cmax, tmax or AUC, using a nonstereoisomeric assay for flurbiprofen. Minor differences in the appearance of flurbiprofen in serum during the first 30‐min post‐dosing period were noted, with Ansaid appearing earlier than Froben. These differences likely reflect dissolution rate dissimilarity between the two products. Stereospecific determinations demonstrate a small (7·8 per cent) but significant difference in AUC of the active S‐configuration (Froben > Ansaid). No significant differences between Ansaid and Froben were found for tmax or Cmax for the S‐flurbiprofen. In bioequivalency studies of chiral drugs, stereospecific approaches provide a more accurate assessment of products.
Prednisone and prednisolone interconversion in the rabbit utilizing unbound concentrations
Authors: Hammarlund‐udenaes Margareta , Benet Leslie Z. 
Published: October 2006

AbstractPrednisolone (POH) and prednisone (PO) were both administered via seven different intravenous infusions (three POH and four PO) in each of six rabbits to obtain steady state. Bolus doses of POH and PO were also administered to four of the rabbits. Plasma samples of POH and PO were analyzed by normal phase HPLC. Unbound concentrations of both compounds were estimated in each rabbit using equilibrium dialysis and computer fit of the nonlinear or linear binding. The unbound fraction of POH ranged between 3 and 15 per cent from tracer to total concentrations of 2000 μg−1. The unbound fraction of PO ranged between 23 and 34 per cent and appeared nonlinear for four of the rabbits. The mean apparent unbound clearances of POH ranged from 4·4 to 6·1 lh −1kg−1 and from 4·1 to 5·9 lh −1kg−1 for PO, and were dose‐independent for both compounds. The available fraction of POH from PO was 50 to 70 per cent and independent of dose. The available fraction of PO from POH averaged 44 per cent at the low infusion rate decreasing to 16 and 20 per cent at the medium and high infusion rates. Although saturability in the formation of PO from POH was noted, this nonlinear step is apparently not large enough to induce observable changes from linearity in the overall disposition of unbound POH.
Pharmacokinetics and bioavailability of papaverine HCl following intravenous, peroral, rectal, vaginal, topical and buccal administration in beagle dogs
Authors: Kraus Christian , Shaaya Ameera , Ulmer Joachim , Hutchings Dawn , Menon Anil , Sakr Adel , Ritschel Wolfgang A. 
Published: October 2006

AbstractThis in vivo study was designed to obtain bioavailability data and a definite pharmacokinetic profile of papaverine HCl in Beagle dogs following intravenous (IV), peroral (PO), rectal, vaginal, topical, and buccal administration of different papaverine HCl formulations. Blood samples were analyzed by high‐performance liquid chromatography. The pharmacokinetic parameters were determined using either a curve fitting program (RESID) or a compartment model independent program (AUC‐RPP). The plasma concentration‐time profiles show that papaverine HCl pharmacokinetics is best described by an open two‐compartment model. The absolute bioavailability of papaverine HCl was determined to be 57·2 per cent, 25·2 per cent, 53·2 per cent, 3·2 per cent and 7·5 per cent, respectively, following P.O., rectal, vaginal, topical and buccal administration.
Partially competitive inhibition of intestinal baclofen absorption by beta‐alanine, a nonessential dietary aminoacid
Authors: Polache A. , Plá‐delfina J. M. , Merino M. 
Published: October 2006

AbstractIn situ intestinal absorption of baclofen in the rat in the presence of beta‐alanine has been investigated. Through the perfusion of 0·50 mM baclofen solutions containing variable concentrations of the aminoacid (from 5 to 100 mM), a partially competitive inhibition of baclofen absorption was characterized: absorption rate pseudoconstants of the spasmolytic drug decrease as beta‐alanine concentration increases, until a limiting value is obtained (36·8 per cent of that found for baclofen alone). A computer method was developed in order to calculate parameters governing baclofen absorption in the presence of beta‐aminoacid, with the following results: Vm = 11·22 mM h−1; Km = 7·42 mM; Ki = 2·45 mM; α = 2·78; r = 0·998. Kinetic absorption parameters for betaalanine in the presence of 0·50 mM baclofen were also assessed: Vm = 49·88 mM h−1; Km = 12·16 mM; r = 0·998, which, as can be expected, do not significantly differ from those previously found in the absence of the spasmolytic. It is concluded that baclofen and beta‐alanine compete for the same intestinal carrier system, although the values of the interaction parameters, particularly Kt, can be more or less biased due to the limitations of the procedure and/or to the existence of some other carrier system for absorption. Possible practical implications of this phenomenon are briefly discussed.
A combined single and multiple dose pharmacokinetic study of oral isosorbide‐5‐mononitrate in healthy volunteers
Authors: Storm G. , Oosterhuis B. , Bron J. , Wittebrood A. J. , De Jong A. P. , Jonkman J. H. G. 
Published: October 2006

AbstractPharmacokinetics of 20 mg isosorbide‐5‐mononitrate (IS‐5‐MN) after single and multiple administration of two different tablet formulations were investigated in twelve healthy human subjects using an open, randomized, two‐way crossover experimental design. Pentacard® 20 mg tablets were compared with Ismo® 20 mg tablets.After single‐dose administration, both preparations caused a rapid increase in IS‐5‐MN plasma levels with the peak plasma concentration occurring between 0·5 and 1·5 h. For both formulations, the mean plasma half‐life was found to be approximately 5 h after a single dose. In steady state during multiple dosing (t.i.d. at 8 h dosing intervals), a reduced elimination rate was observed. In line with this observation, the area under the plasma concentration‐time curve (AUC) for one 8 h dosing interval during multiple dosing was higher than the extrapolated AUC after a single dose. Based on statistical evaluation of the various relevant pharmacokinetic parameters calculated from the plasma concentrations occurring after single and multiple dosing, the tablet formulations are judged to be bioequivalent.
Use of a microbial model for the determination of drug effects on cell metabolism and energetics: Study of citrulline‐malate
Authors: Briand Joël , Blehaut Henri , Calvayrac Régis , Laval‐Martin Danielle 
Published: October 2006

AbstractEuglena gracilis can be used as a microbial model to study the effect of drugs on lactate metabolism and gluconeogenetic synthesis. The cell growth and metabolism have been characterized in a 33 mM lactate medium, non‐supplemented or supplemented by dl‐malate or by l‐citrulline alone or by the compound formed by the stoichiometric combination of the two components: the citrulline‐malate (Stimol®). The malate of the complex accelerated the ammonium disappearance, while the citrulline facilitated the lactate consumption. A synergistic action of the complex, by comparison with the additive effects of the individual components, on most of the parameters studied was detected. A remarkable resistance to anoxia, and a quicker recovery under aeration of the cells supplemented with CM, were evident: after carbonation for 2 min the total nucleotides in the medium were increased by 44 per cent with an unchanged energy charge; and after a prolonged (20 min) anoxia followed by an aeration, the capacities of the cells to synthesize ATP in the presence of excesses of both ADP and phosphate were two‐fold higher in Stimol® treated cells than in control.
Linear pharmacokinetics of haloperidol in the rat
Authors: Cheng Y. F. , Paalzow L. K. 
Published: October 2006

AbstractPharmacokinetics of haloperidol in the rat following intravenous bolus doses of 0·5, 1·0, and 2·5 mg kg−1, respectively, were investigated. It was found that haloperidol was a high extraction ratio drug with a total blood clearance averaging 83 ml min−1 kg−1. The volumes of distribution were large with a mean of 5·5 1 kg−1 (Vc), 11·11 kg−1 (Vβ), and 9·61 kg−1 (Vss), respectively. The terminal half‐life was 1·5h. The disposition kinetics of haloperidol was found to be linear over the dose range studied. After constant intravenous infusions of haloperidol by different infusion rates during 12h, steady‐state levels were reached in the blood. The measured steady‐state blood concentrations were consistent with those predicted by a biexponential infusion model based on the parameters obtained from the intravenous bolus study. The total blood clearance at steady‐state was concentration‐independent within the investigated range of 5 to 20 ng ml−1.
Kinetic analysis of tissue distribution of doxorubicin incorporated in liposomes in rats: I
Authors: Harashima Hideyoshi , Ohshima Shunji , Midori Yukari , Yachi Kiyoto , Kikuchi Hiroshi , Kiwada Hiroshi 
Published: October 2006

AbstractThe purpose of this study was to perform a kinetic analysis of the tissue distribution of doxorubicin (DXR) and liposomes separately after intravenous administration of DXR entrapped in liposomes in rats. Liposomes were double labeled with 14C‐DXR (L‐DXR) and 3H‐inulin (L‐INU). Blood and tissues were sampled at specified times until 120 min. Blood clearance of L‐DXR was similar to that of L‐INU. Distribution of both L‐DXR and L‐INU into the liver was parallel and extensive, while in the heart, the pattern of distribution differed between L‐DXR and L‐INU after peak concentration. Time courses of tissue concentration were explained well by dividing tissue into a shallow compartment with efflux and a deep compartment without efflux. In the liver, pharmacokinetic parameters of L‐DXR and L‐INU were similar, and the two kinetically different compartments may correspond to different uptake processes in hepatic endocytosis. In the heart, the shallow compartment was considered to correspond to the cardiac vascular space, and the intercompartmental rate constant (k3) for L‐DXR was much larger than that for L‐INU. The estimated half‐life for this process was 20 min. The half‐life for the degradation of liposomes in blood circulation was also estimated at 20 min from data on the urinary excretion of released 3H‐inulin. These results suggest that the release of DXR from liposomes may be the rate‐limiting process in the tissue distribution of DXR to the heart.
Absence of food effects on the pharmacokinetics of terfenadine
Authors: Eller Mark G. , Walker Barbara J. , Yuh Lianng , Antony Kelly K. , McNutt Bruce E. , Okerholm Richard A. 
Published: October 2006

AbstractAdministration of terfenadine (Seldane®) immediately after a high fat breakfast slightly affects the rate but not the extent of absorption relative to fasting administration. Mean peak levels of the active metabolite were increased by 13 per cent but delayed by 0·9h while AUC was virtually the same as when terfenadine was administered while fasting. Changes in rate of absorption may be due to delayed gastric emptying and more rapid terfenadine solubilization. In any case, these rate differences are unlikely to be clinically important in the absence of differences in extent of absorption.
Pharmacokinetics of teicoplanin upon multiple dose intravenous administration to normal healthy male volunteers
Authors: Thompson Gary A. , Smithers Jacquelyn A. , Kenny Michael T. , Dulworth Jacqueline K. , Kulmala Henrik K. , Yuh Lianng , Lewis Eric W. , Antony Kelly K. 
Published: October 2006

AbstractTeicoplanin pharmacokinetics were investigated upon multiple dose intravenous administration of 6 and 12 mg kg−1 in 10 normal, healthy, male volunteers, using a two‐period, randomized, crossover design; six subjects completed both periods. On day 1, 6 or 12 mg kg−1 was administered every 12 h as a 30‐min constant rate intravenous infusion (two doses). Starting on day 2, the same dose (6 or 12 mg kg−1) was administered every 24 h for an additional 13 days. Blood and urine samples were collected over 21 days. Serum and urine were analyzed using a microbiological assay. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Following multiple dose intravenous administration of 6 and 12 mg kg−1, median pharmacokinetic parameters included: steady‐state volume of distribution of 1·4 and 1·21 kg−1; total clearance of 12·2 and 14·0 ml h−1 kg−1; renal clearance of 11·1 and 10·3 ml h−1 kg−1; and terminal disposition half‐life of 159 and 155 h, respectively. No statistically significant dose‐related difference was observed. In addition, a cross‐study comparison further supports dose proportionality of teicoplanin upon multiple dose intravenous administration of 3 to 12 mg kg−1.