bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single‐dose comparison of the bioavailabilty of aluminium from two formulations of sucralphate in normal volunteers
Authors: Conway E. L. , O'Callaghan C. , Drummer O. H. , Howes L. G. , Louis W. J. 
Published: October 2006

AbstractThe oral bioavailability of aluminium was compared after administration of 1 g sucralphate as either a tablet or a suspension (1 g/5 ml) in a crossover study in 16 healthy volunteers. Aluminium levels were detectable in all subjects pre‐dose (21.4±8·8 μg 1−1 before tablet; 21·4±7·4 μg 1−1 before suspension) and there was a measurable increase in the plasma concentrations of aluminium in all subjects after administration of the suspension, and in 14 of the subjects after administration of the tablet formulation, with Cmax reached within the first 8 h in most subjects. Plasma levels were still elevated 72 h after dosing. The variability in plasma levels of aluminium was significantly higher after administration of the suspension (CV 39–53%) than after administration of the tablet (CV 29–44%), reflecting greater absorption of aluminium from the suspension formulation in three subjects. Similarly, the variance of the Cmax, AUC(0–72 h), and AUC(0–∞) (for both the raw data and the baseline adjusted data) were all higher for the suspension than for the tablet. A point estimate of the difference of the pharmacokinetic parameters (determined from the median of the arithmetic Walsh averages) indicated little or no difference in Cmax, Tmax, or AUC(0–∞) in the two formulations. In summary, the performance of the suspension formulation of sucralphate is more variable than the tablet formulation in vivo and some patients may therefore have higher circulating levels of aluminium on therapy with the suspension formulation.
Predicting the hepatic clearance of xenobiotics in humans from in vitro data
Authors: Hoener Betty‐Ann 
Published: October 2006

AbstractValues for Vmax and Km determined during the in vitro metabolism of a xenobiotic to a known metabolite by a specific human isozyme of cytochrome P450 (P450) were used to predict the hepatic clearance (CLH) of the xenobiotic to that metabolite. The calculated CLH values were then compared to literature values of clearance (CL) to the same metabolite obtained during pharmacokinetic studies in humans. For the 6‐hydroxylation of chlorzoxazone (P450 2E1) the predicted and actual clearances were 110±77 mL min−1 and 110 mL min−1, respectively. For the 6β‐hydroxylation of cortisol, the deethylation of lidocaine (two studies), and the oxidation of nifedipine (all P450 3A3/4) the values were 13±15 mL min−1 and 13 mL min−1; 758±282 or 829±283 mL min−1 and 875 mL min−1; and 284±176 mL min−1 and 294 mL min−1, respectively. An increase to 72±25 mL min−1 in the CLH of cortisol to 6β‐hydroxycortisol was calculated following rifampicin treatment. Finally, the polymorphic nature of the metabolism (P450 2D6) of mexiletine was confirmed. The usefulness of the method and its limitations are discussed.
Arterial and venous blood sampling in pharmacokinetic studies: Azosemide in rabbits
Authors: Lee Sun H. , Shin Wan G. , Lee Myung G. , Kim Nak D. 
Published: October 2006

AbstractThe pharmacokinetics of azosemide were evaluated simultaneously using both arterial and venous plasma data in six rabbits after a rapid 5 s intravenous bolus dosing. Initial arterial to venous ratios at 5 s after injection were the highest with values of 81.1, 67.3, 58.7, 530, 2660, and 10.5 for rabbits 1–6, respectively. Both curves decayed, paralleling each other at the terminal phase, with the venous levels higher than the arterial levels by 15.3, 31.9, 34.1, 40.7, 30.5, and 16.5% for rabbits 1–6, respectively. An exponential term with a negative coefficient was used to account for the short and steep rising phase of venous plasma levels after injection. Detailed analysis showed significant differences in various pharmacokinetic parameters, such as initial volume of distribution, apparent volume of distribution at steady state, and mean residence time based on arterial or venous data. A plot of 1/Q (urine flow rate) versus l/CLR (renal clearance) of azosemide yielded a straight line in six rabbits, indicating that the CLR of azosemide is urine flow dependent in rabbits.
Influence of γ‐aminobutyric acid on baclofen intestinal absorption
Authors: Nácher A. , Polache A. , Moll‐Navarro M. J. , Plá‐Delfina J. M. , Merino M. 
Published: October 2006

AbstractSince previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by β‐alanine and therefore mediated, at least in part, by the β‐aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a γ‐aminoacid model compound, γ‐aminobutyric acid (GABA). A rat jejunum in situ study was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease as the GABA concentration increases, with a limiting value of 0.65 h−1 (±0.01). A partial competitive inhibition or complete competitive inhibition in the presence of a passive component could define the interaction phenomena between the two substances. Kinetic absorption parameters for GABA in the presence and absence of baclofen (Ki = 5.67 ± 1.54, Km = 3.87 ± 0.63) suggest the existence of more than one intestinal carrier system for baclofen or GABA.
The pharmacokinetics of methotrexate after intravenous administration of methotrexate‐loaded proliposomes to rats
Authors: Park Jeong M. , Ahn Byung‐N. , Yoon Eun J. , Lee Myung G. , Shim Chang‐K. , Kim Chong‐K. 
Published: October 2006

AbstractThe pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) injection of free MTX (treatment I), MTX‐loaded proliposomes (treatment II), and empty proliposomes mixed manually with free MTX (treatment III), 8 mg kg−1, to rats using an HPLC assay. After i.v. infusion in 1 min, the plasma concentration of MTX (Cp), the area under the plasma concentration‐time curve (AUC, 639 versus 913 μg min mL−1), the terminal half‐life (t1/2, 48.8 versus 397 min), the mean residence time (MRT, 8.40 versus 325 min), and the apparent volume of distribution at steady state (Vss, 98.1 versus 2800 mL kg−1) were significantly higher; however, the total body clearance (CL, 12.5 versus 8.76 mL min−1 kg−1), renal clearance (CLR, 4.49 versus 2.78 mL min−1 kg−1), non‐renal clearance (CLNR, 7.50 versus 5.99 mL min−1kg−1), and the amount of MTX excreted in urine (Xu, 808 versus 685 μg, p < 0.0948) were significantly lower from treatment II than from treatment I. This could be due to the fact that some of the MTX‐loaded liposomes (formed immediately after hydration of MTX‐loaded proliposomes) are entrapped in tissues and the rest are present in the plasma (higher MRT and Vss from treatment II), and MTX is slowly released from MTX‐loaded liposomes (higher t1/2 from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX loaded in liposomes (higher Cp and AUC, slower CL from treatment II). After i.v. infusion in 1 min, some pharmacokinetic parameters, such as t1/2, MRT, and Vss, were significantly different between treatments I and III; however, the differences seemed to be smaller than those between treatments I and II. After 30 min from i.v. infusion, the tissue to plasma (T/P) ratios of MTX in kidney and stomach from treatment II were significantly lower than those from treatment I. This suggested that the i.v. administration of MTX‐loaded proliposomes might have fewer side effects in the organs than that of free MTX. The mean amount of MTX loaded in MTX‐loaded proliposomes was 2.54 mg/g proliposomes and the MTX was released slowly from hydrated MTX‐loaded proliposomes when incubated with phosphate‐buffered saline (PBS), rat plasma, or rat liver homogenate.
The influence of chronic lobular hepatitis on pharmacokinetics of cefoperazone—a novel galactose single‐point method as a measure of residual liver function
Authors: Hu Oliver Yoa‐Pu , Tang Hung‐Shang , Chang Ching‐Ling 
Published: October 2006

AbstractCefoperazone is a semisynthetic cephalosporin antibiotic containing a piperazine side chain, which results in antipseudomonal activity. Unlike the other cephalosporins, it is mainly cleared by the liver (60–80%) and it may be more sensitive to changes in the liver function and/or plasma protein binding than other cephalosporins, which are not primarily cleared by the liver. In order to study the influence of chronic lobular hepatitis on the pharmacokinetics of cefoperazone, a dose of 1 g of cefoperazone was administered to 11 normal, healthy volunteers and 16 subjects with chronic lobular hepatitis. In each volunteer or patient, a novel galactose single‐point (GSP) method, the galactose elimination capacity (GEC) test, and the modified galactose elimination capacity (MGEC) test were also performed as a measure of residual liver function. Cefoperazone was administered intravenously over a period of 3–5 min. Blood and urine samples were collected at appropriate intervals after drug administration and stored at −30°C until high‐pressure liquid chromatographic (HPLC) analysis.The cefoperazone hepatic clearance, mean residence time, and renal clearance in hepatitis patients were significantly different from those of normal healthy volunteers, whereas the plasma protein binding was unaltered between the two groups. Urinary excretion of cefoperazone showed a highly significant increase in patients, 23.95 ± 5.06% and 37.54 ± 13.61% for normal men and hepatitis patients respectively. Hepatic clearance and fraction excreted in urine significantly correlated with values of GSP and MGEC respectively (p <0.05). These results suggest (i) cefoperazone kinetics was significantly altered in patients with chronic lobular hepatitis; (ii) GSP, a novel simple, clinically useful quantitative liver function test, can predict the cefoperazone hepatic clearance in patients with liver dysfunction.
Relative bioavailability of two oral formulations of navelbine in cancer patients
Authors: Zhou X. J. , Zhou‐Pan X. R. , Favre R. , Rahmani R. 
Published: October 2006

AbstractA study was carried out in 14 cancer patients to assess the relative bioavailability of two oral formulations of navelbine. A single 130 mg oral dose of the drug was given according to a randomized two‐way crossover design as two capsules: one contained the drug in powder (formulation A, reference); another contained the drug in solution (formulation B). A 7 d washout period separated each dose. Navelbine was rapidly absorbed after administration of either formulation and exhibited a biphasic concentration decay pattern. The peak plasma level was reached within 2 h of administration in most patients. Formulation B resulted in better naveibine absorption with respect to peak plasma concentration (Cmax) and area under the plasma concentration—time curves (AUC) than did formulation A as ascertained by analysis of variance (ANOVA). The relative bioavailabilities (solution versus powder) were, respectively, 286.0% and 268.0% as estimated from experimental (0–72 h) and extrapolated (0–∞) AUC.
Variability in the disposition of chlorzoxazone
Authors: De Vries Jantine D. , Salphati Laurent , Horie Seichi , Becker Charles E. , Hoener Betty‐Ann 
Published: October 2006

AbstractChlorzoxazone is 6‐hydroxylated by cytochrome P450 2E1 (CYP 2E1), which bioactivates many toxic and carcinogenic molecules. Seventeen volunteers of varying age, ethnicity, and gender received a 250 mg tablet of chlorzoxazone and their blood and urine were sampled frequently for 8 h. V/F = 42 ± 21 L and CL/F = 412 ± 120 mL min−1. Comparison of these values with a study by other investigators using a suspension dosage form suggested that relative Ftablet ± 0.7. The fraction excreted in the urine as 6‐hydroxychlorzoxazone (f2,6‐OH) was 0.39 ± 0.20 and that portion of the total CL accounted for by CYP 2E1‐mediated metabolism (CL6‐OH) was 163 ± 95 mL min−1. Thus, while V/F and CL/F varied by factors of less than five, fe,6‐OH varied 16‐fold and CL6‐OH varied 28‐fold. These results suggested that there was considerable inter‐individual variability in the metabolism of chlorzoxazone to 6‐hydroxychlorzoxazone. This variability will significantly affect the construction of physiologically based pharmacokinetic models that use the 6‐hydroxylation of chlorzoxazone as a marker for an individual's CYP 2E1 phenotype.
Relationship between plasma and bone concentrations of cefuroxime and flucloxacillin three different parenteral administrations compared in 30 arthroplasties
Authors: Ferrero Miguel M. Alvarez , Vree Tom B. , Van Ewijk‐Beneken Kolmer Eleonora W J. , Slooff Tom J. J. H. 
Published: October 2006

Abstract
The objective was to determine the range of bone levels of cefuroxime and flucloxacillin achieved after one intravenous (IV) administration of different dosages of cefuroxime and flucloxacillin.
Six groups of five patients participated in the study. The first three groups (A–C) received respectively 1500 mg, 1000 mg, and 500 mg cefuroxime intravenously and the second three groups (D–F) received 2000 mg, 1500 mg, and 1000 mg flucloxacillin intravenously.
Parenteral administration of cefuroxime and flucloxacillin resulted in measurable bone concentrations in all patients.
Large inter‐individual variation in bone concentration was observed.
The bone concentrations of IV cefuroxime were higher (1500 mg, p = 0.0057; 1000 mg, p = 0.0260) than those of flucloxacillin. The bone concentrations of cefuroxime and flucloxacillin were dose dependent.
Pharmacokinetic profile of conjugated verrucarol urinary metabolites in dogs
Authors: Barel Shimon , Yagen Boris , Bialer Meir 
Published: October 2006

AbstractThe pharmacokinetics and renal excretion of a trichothecene mycotoxin, verrucarol, were studied in six mongrel dogs following IV administration (0.4 mg kg−1).The fraction of verrucarol excreted intact in the urine ranged from 0.9% to 2.7% of the administered dose. The fraction of verrucarol metabolites excreted in the urine was 32–60% for verrucaryl glucuronides and 32–47% for verrucaryl sulphates. These urinary conjugated metabolites were analyzed quantitatively following their enzymatic hydrolysis. The half‐life of verrucarol calculated from the urinary data of its conjugated metabolites was not significantly different from the half‐life calculated from the plasma data of the parent compound.
Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV‐1 protease inhibitor, KNI‐272, in rats after intravenous administration
Authors: Kiriyama A. , Fujita K. , Takemura S. , Kuramoto H. , Kiso Y. , Takada K. 
Published: October 2006

AbstractThe pharmacokinetic (PK) characteristics of KNI‐272, a potent and selective HIV‐1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI‐272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI‐272, were examined. After IV administration of 10.0 mg kg−1 KNI‐272, the mean terminal elimination half‐life, t1/2λz, was 3.49 ± 0.19 (SE) h, the total plasma clearance, CLtot, was 15.1 ± 1.2 mL min−1 and the distribution volume at steady state, Vd,ss, was 3790±280 mL kg−1. On the other hand, after 1.0mg kg−1 IV administration, td,ss, was 3.04±0.11 h, CLtot was 15.9±0.2mL min−1, and Vd,ss was 6950±600 mL kg−1. The PK parameters of KNI‐272 after IV administration showed that the disposition of KNI‐272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg−1. Using an equilibrium dialysis method, the plasma binding of KNI‐272 was measured in vitro. The free fractions were 17.7 ± 0.6%, 12.1±1.5%, and 13.8 ± 1.4% at the total concentration ranges of 9.898 ± 0.097 μg mL−1, 0.888 ± 0.008 μg mL−1, and 0.470±0.55 μg mL−1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 ± 1.06% and 1.61 ± 0.32% at 1.0mg kg−1 dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg−1 dose, respectively. The renal clearance (CLR) and the biliary clearance (CLB) were calculated to be 0.191 and 0.256mL min−1 for 1.0mg kg−1, and 0.0248 and 0.215 mL min−1 for 10.0 mg kg−1, respectively. When comparing these values with the CLtot values, the urinary and biliary excretion of KNI‐272 are minor disposition routes.
A biopharmaceutic approach in designing a controlled release tablet of sodium monofluorophosphate: 1. in vitro and in vivo studies in beagle dogs
Authors: Vattikonda Chandra S. , Ritschel Wolfgang A. 
Published: October 2006

AbstractThe purpose of this study was to develop a controlled release tablet (CRT) of sodium monofluorophosphate (NaMFP) based on biopharmaceutic and pharmacokinetic principles. NaMFP was introduced in the early eighties to treat osteoporosis. The required dose size (200 mg of NaMFP) and time of drug delivery (8.3 h) were theoretically determined based on the pharmacokinetic parameters of fluoride (F−). A CRT was formulated with ethyl cellulose (EC) by the direct compression method. The ratio of drug to polymer was adjusted 1:1, after studying the in vitro release profiles. The release mechanism from the developed dosage form followed the square root of time relationship. This dosage form was evaluated for its in vivo performance in dogs. The pharmacokinetics of F−, after the IV and PO administration of NaMFP, was determined to standardize the animal model. F− followed a two‐compartment model and no significant differences were found between the two routes of administration. The bioavailability in dogs was only 60%. The reason for this poor bioavailability was postulated to be the delivery of drug extended beyond the principal sites of absorption of the gastrointestinal tract. Hence, we decided to characterize the absorption sites of NaMFP and to modify the CRT.
Drug distribution and a pulmonary adverse effect of intraperitoneally administered doxorubicin niosomes in the mouse
Authors: Uchegbu Ijeoma F. , Turton John A. , Double John A. , Florence Alexander T. 
Published: October 2006

AbstractNiosomes (non‐ionic surfactant vesicles) prepared from C16G2 (a hexadecyl‐diglycerol ether), and loaded with doxorubicin, were administered intraperitoneally to male AKR mice at dose levels of 0, 2.5, 5.0, and 10.0 mg kg−1. Free drug was given at 10.0 mg kg−1 by the intraperitoneal route. At a dose level of 10.0 mg kg−1, peak doxorubicin levels in the central compartment were attained faster with the free drug than with the niosome formulation. However, the peak plasma levels were similar for the free drug and the niosome preparation at the 10 mg kg−1 dose level. With doxorubicin administered as the niosome preparation by the intraperitoneal route at 2.5, 5.0, and 10.0 mg kg−1, mean peak plasma concentrations of the drug showed a tendency to be dose‐related although the differences were not significant. Over the 24 h period of the experiment, with doxorubicin at 10 mg kg−1, the niosome formulation delivered significantly more drug to the plasma compartment than the free drug (p <0.05). When doxorubicin was given in niosomes at 2.5, 5.0 and 10.0 mg kg−1 by the intraperitoneal route, the resulting levels of doxorubicin in cardiac tissue were not dose related and the differences not significant and, although the mean peak cardiac‐tissue concentration was higher in animals receiving the free drug at 10.0 mg kg−1 intraperitoneally than in mice given intaperitoneal doxorubicin niosomes at this dose level, the differences were again not significant. There were clinical signs of toxicity in mice given doxorubicin‐containing niosomes intraperitoneally at 5.0 and 10.0 mg kg−1, and at post‐mortem an accumulation of fluid in the pleural cavity was evident. These changes were not seen in mice dosed intraperitoneally with free drug at 10 mg kg−1, or in animals given doxorubicin niosomes intraperitoneally at 2.5 mg kg−1. In mice dosed intraperitoneally with doxorubicin niosomes at 12.0 mg kg−1 and at a dose volume of 0.2–0.4 mL, histological examination of the lungs demonstrated a congestion of the alveolar capillaries, and an increased number of acute inflammatory cells in the alveolar walls. There was no histological evidence of lung toxicity in mice dosed with doxorubicin niosomes at 12.0 mg kg−1 when the formulation was administered with the higher dose volume of 1.8–2.0 mL. Importantly there was no histological evidence of lung toxicity in mice dosed with empty niosomes intraperitoneally or with doxorubicin niosomes given itravenously at 12.0 mg kg−1.
Variable gastric emptying and discontinuities in drug absorption profiles: Dependence of rates and extent of cimetidine absorption on motility phase and pH
Authors: Langguth Peter , Lee Kathleen M. , Spahn‐Langguth Hildegard , Amidon Gordon L. 
Published: October 2006

AbstractThe influence of various fasting‐state gastrointestinal parameters on variability in absorption of cimetidine was studied using simulation and cimetidine administration as a duodenal infusion and as an oral tablet in fistulated mongrel dogs. In the simulation studies, the frequency of double‐peak occurrence in plasma profiles was estimated employing average gastric emptying rates as well as interdigestive‐migrating‐motor‐complex (IMMC) phase lengths that were systematically altered. Emptying rates and phase lengths were modeled as periodic step functions. Simulations indicated that double peaks occur when gastric emptying of the drug begins in early phase I or late phase II/III, which represent the periods of very low, medium, and high gastrointestinal motility, respectively. The incidence is increased for longer phase‐I duration and higher elimination rate constants. For a compound with a 2 h elimination or disposition half‐life, two concentration maxima (double peaks) were found in 12% of the simulated concentration‐time profiles. The double peak frequency in simulated curves was considerably higher for t1/2 <30 min. When cimetidine was administered to dogs as a duodenal infusion in the active andquiescent motility phases, discontinuous profiles were observed, although the variability of the various parameters was reduced when compared. Pharmacokinetic models were set up that were characterized by multi‐segmental input (one‐ to 3‐lag‐time models were used) for the profiles resulting from oral and duodenal administration. The lag time for the first process characterized the onset of absorption. A significant difference between phases was detected for infusions at pH 8, where the initial lag time was longer in the quiescent phase. The mean input time (MIT) was calculated as the integral input parameter. There was a tendency for the MIT to be higher for pH 6 infusions than for pH 4 and pH 8. Bioavailability analysis indicated that cimetidine was more rapidly and completely absorbed at pH 8 than at pH 6. Bioavailability was also slightly higher at pH 4 than at pH 6. We concluded that gastric emptying increased the variability of the cimetidine concentration‐against‐time profiles and that it plays a role with respect to double‐peak occurrence, although it is only one of several causative factors.