bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of stobadin and of the sum of its metabolites in rats during repeated administration
Authors: Kállay Zoltán , Šoltés Ladislav , Trnovec Tomáš
Published: October 2006

Stobadin dihydrochloride was administered p.o. to rats at a dose of 1 mg kg−1 once daily for 25 consecutive days. The peak and trough concentrations of the sum of stobadin metabolites, determined from Days 6–16 of treatment, demonstrated a steady‐state. The mean daily excretion of 3H‐radioactivity during this period was 43 per cent and 52 per cent of the administered dose into urine and faeces, respectively. The terminal half‐life of stobadin in plasma following a 25‐day chronic treatment was 78·3 min, which was shorter than the value of 95·3 min, determined in a single dose experiment. The data indicate that no accumulation of stobadin and of its labelled metabolites occurs in the course of repeated administration of 3H‐stobadin.
Endogenous plasma N‐acetylcysteine and single dose oral bioavailability from two different formulations as determined by a new analytical method
Authors: Gabard Bernard , Mascher Hermann
Published: October 2006

A method to quantitate N‐acetylcysteine in plasma using reductive cleavage with tributyl‐phosphine and post‐HPLC column derivatisation with o‐phthalaldehyde is described. Using this method, endogenous average concentrations of 0·08 μM were measured in 10 volunteers participating in a crossover study to compare the bioavailability of two different formulations of N‐acetylcysteine. The drug was detected in plasma for up to 12h after administration of a single oral dose (200 mg); the Cmax values were up to 20 times the endogenous levels. The sensitivity and selectivity of the method should thus enable the behaviour of N‐acetylcysteine after oral administration to be properly described and bioavailability studies to be performed.
Disposition and pharmacodynamics of dichloroacetate (DCA) and oxalate following oral DCA doses
Authors: Curry Stephen H. , Lorenz Anthea , Pei‐ichu  , Limacher Marion , Stacpoole Peter W.
Published: October 2006

Healthy volunteers received intravenous and/or oral doses of sodium dichloroacetate (DCA) in various single and multiple dose regimens. A crossover bioavailability study proved abortive because second and subsequent doses showed significantly longer terminal elimination half‐lives (means 3·64 h and 9·9 h, respectively) than was the case for initial doses (1·58 h). A parallel bioavailability comparison failed to show that oral doses were significantly different from 100 per cent bioavailability (AUCoral, 604μgh−1 ml−1; AUCi.v., 489μgh−1 ml−1). The time required to elapse between individual doses, in order to prevent second doses having relatively long half‐life values, varied in different individuals from 1 week to greater than 3 months. No cardiac or central nervous system effects were recorded by echocardiography and digit symbol substitution tests, respectively. The mean renal clearance of DCA was 42·9 ml h−1. No differences were observed in DCA kinetics between male and female subjects.
Bioavailability of diltiazem as a function of the administered dose
Authors: Bianchetti G. , Regazzi M. , Rondanelli R. , Ascalone V. , Morselli P. L.
Published: October 2006

Diltiazem undergoes extensive first‐pass metabolism; extrapolation from single to repeated administration thus underestimates plasma concentration values. In order to validate the hypothesis of a partially saturable first‐pass effect, four single doses of diltiazem (10, 20, 40, and 120 mg) were administered at weekly intervals to eight healthy volunteers. Results showed that: (a) the inter‐subject variability was highest at the lowest dose and lowest at the highest dose; (b) bioavailability was almost nil in 3 of 8 of the subjects after the administration of the 10 mg dose; (c) the mean bioavailability increased with the dose from 11·8 ± 2·5 per cent after 10 mg to 28·2 per cent after 120 mg; (d) the elimination half‐life was dose‐related; (e) the renal excretion of diltiazem increased with the administered dose from 1.0 ± 0·3 per cent after 10 mg to 3·0 ± 0·5 per cent after 120 mg; (f) the greatest amounts of circulating metabolites were present after the lowest doses. These results are consistent with a partially saturable first‐pass effect for diltiazem.
Ocular pharmacokinetics of calcium, chloride and sulphate ions after instillation in the rabbit
Authors: Hariton C. , Mandel P.
Published: October 2006

The ionic environment of the eye is involved in major biochemical processes which are essential for preserving the integrity of cornea and lens. The purpose of the present study was to determine the intra‐ocular penetration and the pharmacokinetic parameters of calcium, chloride and sulphate ions in the cornea, iris‐ciliary body (ICB) and lens, after administration by instillation in the rabbit eye. In order to extrapolate our results to the processes occurring in man, we followed a precise instillation protocol using a low volume (5 μl) of 45Calcium, 36Chloride and 35Sulphate, which is less than the lacrimal volume determined during the palpebral closing and performing manual blinking at a frequency of 2 min−1

The results indicate an immediate trans‐corneal permeability and a rapid ocular distribution of these ions. We observe that, relative to dose, an important percentage of calcium (67·20 per cent) was entrapped in the cornea; this parameter was less important for chloride (10·19 per cent) and for sulphate ions (3·25 per cent). These values are in agreement with those predicted theoretically for trans‐corneal penetration by such compounds. On the other hand, the total degrees of penetration by chloride and sulphate ions in ICB (1·40 per cent and 0·90 per cent, respectively) and lens (0·35 per cent and 0·41 per cent, respectively) are quite similar. Calcium retention is much higher in these tissues (25·39 per cent in ICB and 16·03 per cent in lens). It seems likely that the higher degree of lens entrapment of calcium may be explained by the trans‐capsular electrical potential difference and the negative charge inside the lens and the presence of proteins possessing high affinity and binding capacity for calcium.
Diclofenac, paracetamol, and vidarabine removal during plasma exchange in polyarteritis nodosa patients
Authors: Fauvelle F. , Nicolas P. , Leon A. , Tod M. , Perret G. , Petitjean O. , Guillevin L.
Published: October 2006

Since plasma exchange (PE) represents a major treatment for patients suffering from systemic diseases, its influence on the kinetics of three drugs was investigated: vidarabine, used in patients with polyarteritis nodosa associated with hepatitis B virus (eight subjects), and diclofenac and paracetamol for investigative purposes (five subjects). This study confirmed that vidarabine is so rapidly deaminated to form hypoxanthine arabinoside (Hx‐Ara) that no detectable concentrations were measured. Hx‐Ara levels were used to evaluate vidarabine kinetics; 19·5 ± 14·6 mg of Hx‐Ara were removed by one PE during the first week of treatment (15 mg kg−1 d−1, continuous infusion) and 7·8 ± 10·2 mg were eliminated by one PE during the second week of treatment (7·5 mg kg−1 d−1, continuous infusion). Based on the vidarabine intake per hour and the resulting quantity of Hx‐Ara removed per hour, PE recovery was quite important (ca. 30 per cent), during both the first and second weeks of continuous infusion. Data were subject to large interindividual variability. However, these results do not favor vidarabine dosage supplementation in this indication because the duration of PE is less than 8 per cent of a daily administration period. For paracetamol (1 g, single oral dose) and diclofenac (100 mg, single oral dose), the fractions of drug removed during PE effected within 2 h of drug intake, were respectively 5·0 ± 3·1 per cent and 13·6 ± 9·5 per cent, while plasmapheretic clearance reached, respectively, 13·0 ± 10·7 per cent of the systemic clearance for paracetamol and 23·0 ± 1·0 per cent for diclofenac.
Effect of co‐administration of intralipidTM on the pharmacokinetics of cyclosporine in the rabbit
Authors: Shah Ajit K. , Sawchuk Ronald J.
Published: October 2006

The effect of IntralipidTM co‐administration on the pharmacokinetics of cyclosporine (CyA) was studied in NZW rabbits. A single intravenous bolus dose of CyA (10 mg kg−1) mixed with 3 ml of Intralipid was administered to rabbits (n = 4). Control animals (n = 4) received the same dose of CyA without Intralipid. Serial blood samples were collected up to 12 h after the administration of CyA. Concentrations of CyA in plasma were analyzed using a HPLC method. The terminal elimination half‐life (t1/2) of CyA was significantly lower with Intralipid administration (191·25 min) than control (298 ± 59 min). The total body clearance (C1TOT) and volume of distribution (Vdss) of CyA was reduced by approximately 65–70 per cent with Intralipid administration compared to control. The free fraction of CyA in plasma with and without Intralipid administration was estimated to be 0·05 ± 0·01 and 0·17 ± 0·06, respectively. Co‐administration of Intralipid with CyA decreased both the ClTOT and Vdss resulting in a rapid elimination, i.e., decrease in a t1/2 of CyA from the body.
Relative bioavailability of oral sustained‐release and regular‐release oxprenolol tablets at steady‐state
Authors: Gupta P. K. , Lim J. K. C. , Zoest A. R. , Lam F. C. , Hung C. T.
Published: October 2006

The relative bioavailability of a test sustained‐release (SR) oxprenolol tablet against an approved regular‐release (RR) tablet has been investigated at steady‐state. In a randomized two‐way crossover study, one tablet of 160mg SR oxprenolol once every 24 h and one tablet of 80 mg RR oxprenolol once every 12 h were given to 12 healthy volunteers for 5 days. Blood samples were collected from each subject just prior to each dose‐administration on days 1 through 4, and at scheduled time points on day 5 and analysed for oxprenolol concentration using HPLC. The SR tablet resulted in 42 per cent reduction in mean peak drug levels (p = 0·0341) and a statistically non‐significant 14 per cent increase in mean trough levels (p = 0·8357) than the RR tablet. However it required 160 per cent longer time to reach average steady‐state concentrations (CSS) on day 5 (1·38h for SR versus 0·53 h for RR; p =0·0205). The mean area under the plasma drug concentration—time curve at steady state (AUC96‐120) with the SR tablet was ∼ 18 per cent lower than that observed with the RR tablet, and the degree of fluctuation (DF) was reduced by 30 per cent (2·81 for SR versus 4·11 for RR;p = 0·0069). On average, a single dose of SR tablet and two doses of RR tablets maintained the drug levels above a constant CSS of 204·6 ngml−1 for 7·88 and 7·65 h, respectively (p = 0·3513).
Pharmacokinetics of diltiazem and propranolol when administered alone and in combination
Authors: Dimmitt Dan C. , Yu Dale K. , Elvin Alfred T. , Giesing Dennis H. , Lanman Robert C.
Published: October 2006

Multiple oral doses of diltiazem (DTZ) and propranolol (PPL, 60 mg every 8 h daily for 13 doses) were administered to 14 healthy volunteers alone and in combination on three separate occasions. Serial blood samples were collected up to 24 h after dose 13 on day 5 to determine possible pharmacokinetic interactions between the two drugs. When administered alone, DTZ concentration peaked at 161·4 ng ml−1 3 h following the final dose with an elimination half‐life of 6·1 h. DTZ oral clearance was 65·11 h−1. PPL did not affect DTZ oral clearance and half‐life during the combination treatment. However, DTZ tmax was extended from 2·9 h to 3·5 h (p < 0·05) and Cmax was 144·7 ng ml−1. Unlike the parent drug DTZ, desacetyldiltiazem (DAD) plasma profile was elevated during the combination treatment. DAD Cmax and AUC both increased approximately 20 per cent (p < 0·05). PPL pharmacokinetics were altered as well. Oral clearance of PPL decreased from 80·4 1 h−1 to 61·0 1 h−1 while the half‐life increased from 5·9 h to 8·0 h (p < 0·05). PPL Cmax increased from 155·1 ng ml−1 to 167·5 ng ml−1.
Isomazole disposition in man as a function of dose and route of administration
Authors: Woodworth James R. , Delong A. F. , Fasola A. F. , Oldham S.
Published: October 2006

The disposition of a new cardiotonic agent (isomazole (ISO)) was evaluated in healthy volunteers after various single oral (p.o.), intravenous (i.v.), and multiple p.o. doses. Blood samples were collected after dosing in all studies, with urine collected in the single i.v. and multiple dose studies. All biological samples were measured for ISO. In the multiple dose study, samples were collected for analysis after the first and last doses administered. In addition to ISO, several known metabolites (hydroxyisomazole (OHISO), sulfone (SULF), and hydroxysulfone (OHSULF) analogs) were measured after the first and last doses given in the multiple dose study. Pharmacokinetic values compared between doses suggested no saturable processes existed over the entire dose range. The single i.v. dose data showed ISO experienced some extravascular distribution (mean Vβ = 1·82 1 kg−1), with a high clearance (mean (Cls = 18·8 ml min−1 kg−1) and a short half‐life (mean t1/2 = 1·1 h). Elimination was primarily nonrenal (Clr = 3·5 ml min−1 kg−1). Single p.o. data supported these findings and further suggested rapid absorption. ISO data from the first dose of the multiple dose study was in agreement with these data; however, the last dose showed a higher Cls (33·0 ml min−1 kg−1) (p = 0·055). Although not statistically significant, metabolite plasma data and urinary excretion patterns changed. An increase was observed in plasma AUC and metabolite excretion of SULF and OHSULF, while a decrease was observed in the same parameters for OHISO. These results suggest that multiple dosing of ISO produces autoinduction of ISO metabolism through selective metabolic routes.
Methimazole increases the plasma concentrations of the albendazole metabolites of netobimin in sheep
Authors: Lanusse Carlos E. , Prichard Roger K.
Published: October 2006

The influence of methimazole (MTZ) on the pharmacokinetics of netobimin (NTB) and its metabolites was investigated in adult sheep. NTB zwitterion suspension was administered at 20 mg kg−1by intraruminal injection either alone or with simultaneous administration of MTZ intramuscularly at 1·5 mg kg−1. Blood samples were taken serially over a 120‐h period and plasma was analyzed by HPLC for NTB, albendazole (ABZ), albendazole sulphoxide (ABZSO), and albendazole sulphone (ABZSO2). NTB parent drug showed fast absorption, low area under the plasma concentration—time curve (AUC) and was rapidly removed from plasma after both treatments. The presence of MTZ did increase significantly the ABZ AUC (138 per cent) and mean residence time (MRT) (86 per cent). Concomitant treatment with MTZ resulted in a notably higher ABZSO plasma profile with significantly longer elimination half‐life (t1/2β) (390 per cent) and MRT (252 per cent) and with significantly higher AUC (95 per cent). Also, MTZ induced significant increases in ABZSO2t1/2β, AUC, and MRT.

We have demonstrated a pharmacokinetic interaction between MTZ and NTB metabolites. MTZ may alter the liver biotransformation of ABZ metabolites which results in pronounced changes in the disposition kinetics of anthelmintically active metabolites.
A general method for calculating the mean transit times and distribution rate parameters of catenary metabolites
Authors: Cheng Haiyung
Published: October 2006

A general method for calculating the mean transit times and distribution rate parameters is described. The calculations require the AUC, AUMC, and derivatives of the plasma concentration profiles of the metabolites and its precursor. The method is applicable to catenary metabolites with any precursor order and does not require separate administration of the metabolite. The approach is applied to published data for the primary and secondary metabolites of ketamine.
Methylxanthine levels in breast milk of lactating women of different ethnic and socioeconomic classes
Authors: Blanchard James , Webr Charles W. , Shearer Luz‐E.
Published: October 2006

The purpose of this study was to evaluate the dietary caffeine and dimethylxanthine concentrations in breast milk of 40 mothers from different ethnic and socioeconomic backgrounds. Their diets and drug intake were not restricted in any way. Each nursing mother provided a fasting and a combined breast‐milk sample each day for 3 consecutive days. No significant differences were found in intake levels of any of the methylxanthines among the groups tested. No significant differences were found among the four groups in breast‐milk levels of caffeine, theobromine, or paraxanthine. However, the mean theophylline milk levels were significantly higher on 2 of the 3 days examined in Anglo‐American woman compared to Hispanic‐American women. Socioeconomic and ethnic variables were also compared among the four groups. The daily amounts of methylxanthines found in the breast milk of this free‐living population of mothers do not appear to present clinically significant amounts to the infant.
Pharmacokinetics of ketoprofen in rats: Effect of age and dose
Authors: Satterwhite Julia H. , Boudinot F. Douglas
Published: October 2006

The effects of age and dose on the pharmacokinetics of ketoprofen were evaluated in young adult and senescent male Fischer 344 rats following intravenous administration of 2·5 and 10 mg kg−1. Plasma concentrations were measured by HPLC and free ketoprofen determined by equilibrium dialysis. The glucuronidation of ketoprofen was investigated in a preparation of rat liver microsomes and kinetic analysis of UDP‐glucuronyltransferase was carried out by determining the initial rate of metabolic activity as a function of ketoprofen concentration. Mean plasma clearance CLfree and steady‐state volume of distribution V calculated from unbound plasma ketoprofen concentrations were significantly lower in the aged rat, suggesting reduced metabolic activity and decreased ketoprofen binding to tissue components, respectively. Plasma protein binding demonstrated an age‐dependent decline due to decreases in both albumin concentration and binding affinity. Thus, plasma clearance CL and steady‐state volume of distribution Vss changes were insignificant when total plasma concentrations were examined, due to the greater free fraction of ketoprofen in the plasma of senescent rats. The maximal rate of ketoprofen glucuronidation by hepatic microsomes was reduced whereas the affinity of the metabolic enzymes for the compound was unaffected by age. Dose had a marked effect on the disposition of ketoprofen as well. Saturation of elimination pathways and tissue binding sites contributed to significant declines in CLfree and V with increasing dose. Likewise, concentration‐dependent plasma protein binding occurred, reflecting saturation of albumin binding. Thus, changes in the pharmacokinetic parameters based on total drug concentrations were offset by the increase in the unbound fraction of ketoprofen.
Distribution kinetics of FK‐506, a novel immunosuppressant, after intravenous administration to rats in comparison with cyclosporin A
Authors: Takada Kanji , Usuda Hisato , Oh‐Hashi Mamoru
Published: October 2006

The distribution kinetics of a novel potent immunosuppressant, FK‐506 (FK) has been studied in comparison with cyclosporin A (CyA) both in vivo and in vitro using blood specimens. The infusion studies on FK, 5·0 mg kg−1 through the portal and femoral veins showed that the mean hepatic extraction ratio of FK was 27·9 per cent. The effect of clamping both the hepatic artery and the portal vein on the plasma disappearance profiles of FK, 5·0 mg kg−1, and CyA, 3·5 mg kg−1 was studied. The plasma disposition kinetics of CyA was almost the same as in the normal rats. However, the plasma FK levels were about 10 times higher than those obtained in the control group rats. This difference is attributed to the restricted initial distribution of FK to the liver, because the volume of the initial distribution space, V1, of FK was about 10 times smaller than that obtained in normal rats. In in vitro experiments, drug distribution was studied in blood samples (2·0 ml) spiked with FK or CyA, 1·0 μg ml−1. The plasma drug levels measured at 2 min after drug administration were 0·842±0·012 μg ml−1 and 0·769±0·047 μg ml−1 for FK and CyA, respectively. The distribution volume in the blood compartment, VB, was determined by dividing the spiked amount of drugs with these plasma concentrations. The VB was 2·38±0·04 ml for FK and 2·62±0·16 ml for CyA. There was no significant difference in VB between FK and CyA. The plasma free fraction, fp of the drugs was measured by the equilibrium dialysis method. For FK, the mean fp values (±SE) were 1·31±0·18 per cent (2·0 μg ml−1) and 1·93±0·18 per cent (5·0 μg ml−1). For CyA, the fp values were 4·85±0·36 per cent (1·0 μg ml−1) and 5·75±0·82 per cent (5·0 μg ml−1). The hydrophobicity parameter, logP′ determined through the HPLC method was 0·386 for FK and 0·545 for CyA. Although FK was less hydrophobic than CyA, its protein binding was higher than CyA.
Rapid toxicological model for use in assessing ocular drugs
Authors: Ellingson Cynthia M. , Schoenwald Ronald D. , Barfknecht Charles F. , Rao Chakradhara S. , Laban Saad L.
Published: October 2006

Nonsteroidal antiinflammatory drugs (NSAIDs) were applied to corneas either by in vitro or in vivo methods. The in vitro method involved excising and mounting corneas in a perfusion system at 37° and exposing drug for 2·5h. The in vivo methods represent either topical administration to the rabbit eye or topical in vivo infusion using a fixed well which permitted a constant concentration (0·05 per cent) to be applied to the eye of anesthetized rabbits for up to 120 min. An overlay grid procedure using scanning electron microscopy (SEM) showed less per cent endothelial damage with in vivo methods than with the in vitro method of administration, but per cent damage depended on which section was viewed. Damage to the epithelium and endothelium were also assessed by quantitative carboxyfluorescein and Janus green staining and uptake procedures, respectively, following drug exposure by the in vivo infusion method. Results for the epithelium indicated that the more lipophilic NSAIDs damaged the epithelial layer to a greater degree than newly synthesized hydrophilic NSAIDs. Damage to the epithelium correlated to the surface activity of the NSAIDs. Qualitative assessment of epithelial and endothelial toxicity can be performed with SEM and transmission electron microscopy (TEM) while vital staining procedures and the SEM grid procedure can be used to quantitatively assess corneal toxicity. The staining methods, however, possess advantages over SEM and TEM procedures in that they are rapid and do not require laborious preparation. As a result of these characteristics, the vital staining procedures could be used as part of a biopharmaceutical screening technique in evaluating new ophthalmic drugs.
Studies on the intravenous pharmacokinetics in rabbit and in vitro protein binding of two new salts of erythromycin: Erythromycin maltobionate and erythromycin fumarate
Authors: Basu S. K. , Manna P. K. , Goswami B. B.
Published: October 2006

Pharmacokinetics in rabbits following intravenous administration and in vitro protein binding were studied for two new salts of erythromycin (erythromycin maltobionate and erythromycin fumarate). Serum erythromycin levels following intravenous injection were described by two compartment model kinetics, and values for the distribution volume of the central compartment, the peripheral compartment and overall distribution volume were calculated. The elimination half‐lives of erythromycins in serum were 83 min, 168 min, and 103 min for erythromycin maltobionate, erythromycin fumarate, and erythromycin lactobionate (reference standard), respectively. The erythromycin salts were highly (c. 90 per cent) protein bound, but the binding was found to be reversible. Differences in the pharmacokinetic parameters after administration of equivalent doses of the salts, indicate possible variation in efficacies of different salts.
Simultaneous modelling of mexiletine and hydroxy‐methyl‐mexiletine data after single‐ and multiple‐dose administration of a sustained‐release mexiletine formulation
Authors: Bruno R. , Santoni Y. , Iliadis A. , Djiane P. , Serradimigni A. , Cano J. P.
Published: October 2006

The pharmacokinetics of mexiletine and its metabolite hydroxy‐methyl‐mexiletine have been investigated following single‐dose and during multiple‐dose administration of a sustained‐release form of mexiletine to six post‐myocardial infarct patients. Comparison of single‐dose and washout pharmacokinetics, after short‐term multiple‐dose administration, showed significant (p<0·005), but not systematic, modifications in mexiletine apparent clearance for three patients. Furthermore, for these patients, simulation with both sets of parameters indicated that the steady‐state was achieved before washout experiment in two cases. The fraction of mexiletine metabolized to hydroxymethyl‐mexiletine was lower for multiple‐dose administration (about 18 per cent) than for the single dose (about 42 per cent). The hydroxy‐methyl‐mexiletine elimination rate constant was about four times that of mexiletine. Mexiletine clearance could be accounted for by other metabolic pathways. In one patient, hydroxy‐methyl‐mexiletine was undetectable even during multiple‐dose administration, despite a significant increase in mexiletine clearance. However, the observed changes in mexiletine disposition had no therapeutic implications and active plasma levels were achieved by the third day of administration and maintained in the therapeutic range (0·75 to 2 μg ml−1) in all patients after a twice daily dosage regimen.
Pharmacokinetics of oxatomide given percutaneously to healthy volunteers
Authors: Benvenuti C. , Broggini M. , Botta V. , Valenti M. , Broccali G. , Bo L. Dal
Published: October 2006

The percutaneous absorption of oxatomide gei at 5 per cent concentration was studied after single and repeated administration (85 mg b.i.d.) in six male and six female healthy volunteers, aged 25·7 ± 0·8 years (mean ± SEM) weighing 64·4 ± 4·5 kg and the results compared with those obtained following a single oral dose (30 mg). The measurement of oxatomide was by means of a new sensitive and specific HPLC assay with limits of detection of 0·2 ng ml−1 in plasma and 1·0 ng ml−1 in urine. Poor percutaneous absorption was confirmed by the peak plasma concentrations which were 5·03 ± 0·79 ng ml−1 following application of the gel for 7 days and 10·08 ± 1·29 ng ml−1 following oral administration; the corresponding amounts of unchanged oxatomide recovered from 24 h urine collections were 1·42 ± 0·39 μg and 3·93 ± 0·92 μg.
In vivo evaluation of the effect of the size and opsonization on the hepatic extraction of liposomes in rats: An application of Oldendorf method
Authors: Harashima Hideyoshi , Ohnishi Yuriko , Kiwada Hiroshi
Published: October 2006

In the hepatic uptake of large particles such as liposomes, a serum component called opsonin plays an important role. In this study, the ‘Oldendorf method’ is introduced to evaluate the hepatic extraction under the condition of single passage, which enabled examination of the effect of opsonization on liposome uptake by the intact liver. 14C‐labelled liposomes and, an internal reference, 3HH2O were injected as a bolus into portal vein. Liver uptake index (LUI) was calculated from the ratio of the extraction of 14C to that of 3H. The effect of liposome size (mean diameter of 0·8, 0·4, 0·2, and 0·05 μm) and opsonization (preincubation with fresh blood for 5 min) on liposomal hepatic uptake were investigated using this method. LUI increased with size significantly (p<0·001), and opsonization enhanced LUI only for the large liposomes (0·8 μm). This result suggests that the critical diameter of opsonization for these liposomes lies between 0·4 and 0·8 μm.
Comparative bioavailability and steady state fluctuations of tegretol commercial and carbamazepine oros tablets in adult and pediatric epileptic patients
Authors: Thakker Kamlesh M. , Mangat Surinder , Garnett William R. , Levy René H. , Kochak Gregory M.
Published: October 2006

The comparative bioavailability and steady state fluctuations resulting from the administration of Tegretol 200 mg commercial tablets and carbamazepine OROS controlled delivery tablets were investigated in 22 adult and 12 pediatric epileptic patients. Tegretol commercial tablets were dosed according to previously established clinical regimens of 400 to 2000 mg daily doses divided into four equal or unequal intervals. Carbamazepine OROS was dosed every 12 h at the same corresponding daily dose. Comparisons of the pharmacokinetic parameters AUC, Cmax, Cmin, and tmax at steady state for the two dosage forms demonstrated definitively the bioequivalence of carbamazepine OROS with Tegretol commercial tablet over a 24‐h treatment interval.
The metabolism of CGS—15873 in man using stable isotope pattern recognition techniques
Authors: Leal M. , Hayes M. J. , Powell M. L.
Published: October 2006

CGS 15873 is a relatively specific dopamine agonist with preferential activity at the presynaptic autoreceptor and therefore may represent a novel agent for the treatment of schizophrenia and/or Parkinson's disease. Several metabolites have been identified in the rat and monkey using an isotopically enriched dosing solution and pattern recognition techniques coupled with GC/MS and LC/MS. In this study, the metabolism of CGS 15873 was investigated in man using these same techniques. In urine, specific isotope clusters were found that matched the dosing solution pattern. Three metabolites were identified: an O‐glucuronide conjugate of the parent drug, N‐despropyl CGS 15873, and a keto metabolite of CGS 15873. Thermospray LC/MS allowed for the direct confirmation of the conjugated metabolite. GC/MS required derivatization but afforded greater sensitivity compared to LC/MS.
Human dolasetron pharmacokinetics: I. Disposition following single‐dose intravenous administration to normal male subjects
Authors: Boxenbaum Harold , Gillespie Todd , Heck Kathleen , Hahne William
Published: October 2006

Dolasetron is a 5‐hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy‐induced nausea and vomiting. Following intravenous administration to healthy male subjects of doses ranging from 0·6 to 5 mg kg−1 dolasetron disappeared extremely rapidly from plasma; concentrations were generally measurable for only 2‐4 h. Less than 1 per cent of the dose was excreted intact in urine. A major plasma metabolite, reduced dolasetron, peaked rapidly at approximately 0·625h. (median). Its median terminal disposition half‐life was 7·56 h; median values for fraction of dose excreted in urine and renal clearance were 31·0 per cent and 2·68 ml min−1 kg−1, respectively. Over the dose‐range covered, pharmacokinetics of both dolasetron and reduced metabolite appeared to be independent of dose. The median ratio of the areas under the plasma concentration‐time curves for metabolite relative to dolasetron was 11·9. As a result of its activity and significant plasma concentrations, reduced dolasetron may play a significant role in pharmacodynamic activity.
Plasma concentrations and hemodynamic effects of intravenous, sublingual, and aerosolized nitroglycerin in patients undergoing cardiac catheterization
Authors: Curry Stephen H. , Lopez Larry M. , Lambert Charles R. , Kwon Hae‐Ryun , Stack Robert K.
Published: October 2006

Intravenous, sublingual, or aerosolized nitroglycerin was administered to 19 patients with coronary artery disease during clinically indicated cardiac catheterization. Eight blood samples were collected over 15 min from each patient, and analyzed for content of nitroglycerin, 1,2‐glycerol dinitrate, and 1,3‐glycerol dinitrate. Simultaneously, heart rate (HR), systolic blood pressure (SBP), and left ventricular end‐diastolic pressure (LVEDP) were recorded. Plasma concentrations of nitroglycerin were highest after intravenous injection and lowest after sublingual tablets. Metabolite concentrations were highest after intravenous injection at early time‐points; at later time‐points, no betweengroup differences could be detected. SBP was minimally affected by intravenous nitroglycerin but was significantly reduced by sublingual and aerosolized formulations. Minor fluctuations in HR were observed in association with all three formulations. LVEDP was reduced by all three formulations of nitroglycerin but most rapidly by the intravenous form. Overall, no differences were detected in hemodynamic responses caused by sublingual and aerosolized nitroglycerin. Efficacy of sublingual and aerosolized nitroglycerin in patients undergoing cardiac catheterization is equivalent.
Ceftriaxone pharmacokinetics in elderly subjects and penetration into epididymis
Authors: Geny Florence , Costa Pierre , Bressolle Francoise , Galtier Marc
Published: October 2006

In a prospective study, the epididymal penetration of ceftriaxone was evaluated in order to use it in the treatment of orchi‐epididymitis in men. A bolus intravenous dose of 1 g of ceftriaxone was administered to 15 patients hospitalized for surgery as part of treatment for prostatic adenoma or prostatic cancer. Nine successive blood samples were collected in the interval from 0 to 24 h after administration, and epididymis samples were taken 0.75 h after administration. Concentrations of drug in all samples were assayed by a reverse‐phase‐ion pairing high‐performance liquid chromatography method with UV detection. The results showed that the pharmacokinetics of ceftriaxone in serum did not differ from those determined previously in healthy volunteers. The terminal half‐life was 6.9 ± 1.7 h, and the mean residence time 9.5 ±2.3 h. The volume of distribution was 0.144 ± 0.018 1 kg−1 and the total body clearance 1.17 ± 0.29 1 h−1. The concentrations in tissue reached 27.2 ± 6μg g−1 in right epididymis, and 25.4 ± 6.2 μg g−1 in left epididymis. The tissue‐versus‐serum concentration ratios ranged from 0.175 to 0.545 (mean value, 0.295 ± 0.099). The concentrations in serum and tissue observed in this study were in excess of the MICs for bacteria considered to be susceptible to ceftriaxone, particularly Neisseria gonorrhea and coliform bacteria.
Biopharmaceutical evaluation of transnasal, sublingual, and buccal disk dosage forms of butorphanol
Authors: Shyu Wen Chyi , Mayol Robert F. , Pfeffer Morris , Pittman Kenneth A. , Gammans Richard E. , Barbhaiya Rashmi H.
Published: October 2006

A series of three‐way crossover randomized studies were conducted to evaluate the absolute bioavailability of butorphanol, a potent agonist‐antagonist analgesic, from transnasal, sublingual, and buccal disk formulations in order to identify a practical alternative to oral administration. In each study, healthy male volunteers received 2 mg doses of butorphanol tartrate intravenously and either transnasally, sublingually or buccally. Serial blood samples were collected over 12 h and butorphanol plasma concentrations were determined by radioimmunoassay. The plasma concentration data were subjected to non‐compartmental pharmacokinetic analysis. The elimination half‐life of butorphanol was about 3–5 h and was independent of the route of administration. Absorption of butorphanol following transnasal administration was faster than that observed following sublingual or buccal administration. Mean absolute bioavailabilities of sublingual tablet and buccal disk formulation were only 19 per cent and 29 per cent, respectively, but for transnasal administration the value rose significantly, to 70 per cent. Based on the results of these studies, transnasal dosage form of butorphanol was selected for further clinical trials of treatment of moderate to severe pain.
Pharmacokinetics of diacerein in patients with liver cirrhosis
Authors: Magnard O. , Louchahi K. , Tod M. , Petitjean O. , Molinier P. , Berdah L. , Perret G.
Published: October 2006

The pharmacokinetics of diacerein following a single oral dose of 50 mg was studied in 12 healthy volunteers, 10 patients with a mild liver cirrhosis (Child Pugh's grade A), and 6 patients with a more severe liver cirrhosis (Child Pugh's grade B to C). Statistical analysis using a Kruskal‐ Wallis test showed no significant differences between the three groups for the following parameters: median Cmax was 3.9 mg l−1 for the cirrhotic patients group I (CPI) and 3.2 mg l−1 for the cirrhotic patients group II (CPII) versus 3.2 mg l−1 for the healthy volunteers (HV); median t1/2 was 4.9 h for CPI and 4.3 h for CPII versus 4.3 h for HV; median Cl/F was 2.1 l h−1 for CPI and 2.5 l h−1 for CPII versus 1.6 l h−1 for HV; median Vdss/F was 12.6 l for CPI and 14.01 for CPII versus 13.2 l for HV. The urinary parameters were comparable. It was concluded that, from a pharmacokinetic point of view, no reduction in the initial dosage of diacerein need be proposed in liver cirrhosis.
Relative bioavailability of two disopyramide capsules in humans based on total, unbound, and unbound enantiomer concentrations
Authors: Takahashi Harumi , Ogata Hiroyasu , Shimizu Mikiko , Hashimoto Kayoko , Masuhara Keiso , Kashiwada Kazuko , Someya Kazuhiko
Published: October 2006

The relative bioavailability of two 100‐mg disopyramide formulations which showed almost an 8‐ to 10‐fold difference in their dissolution rates at pH 1.2 and 6.8 was determined in eight healthy subjects using a randomized block design. Although no significant differences in relative bioavailability were observed between the two formulations when based on the total disopyramide concentration, an almost 30 per cent difference in the extent of bioavailability was observed when assessed in terms of the unbound (±)‐ and (−)‐disopyramide concentration, due probably to stereoselective nonlinear plasma protein binding. This suggests that unbound enantiomer parameters would be more sensitive to differences in bioavailability between two disopyramide formulations. Therefore, the type of concentration used would be an important factor for precise evaluation of the relative bioavailability of racemic drugs.
Bioavailability of intramuscularly administered tenoxicam
Authors: Stebler T. , Guentert T. W.
Published: October 2006

Bioavailability of intramuscularly administered tenoxicam relative to single oral and relative to intravenous doses was determined in two separate randomized crossover studies. Twelve healthy volunteers (12 males, age 20–30 years) received a rapid intravenous injection and a single intramuscular dose and 12 other subjects (11 males, 1 female, age 21–25 years) a single oral and a single intramuscular dose of 20 mg of tenoxicam on two different occasions. The wash‐out period between the two consecutive treatments was 4 weeks. Plasma concentrations after dosing were determined by a specific HPLC method.

Differences in tenoxicam concentration‐time profiles after the different routes of administration were limited to the first 2 h after dosing. Later, plasma concentrations were almost superimposable within and across the two studies. The extent of absorption of intramuscularly administered tenoxicam was complete (mean ± CV per cent: Fabs 0.99 ± 20 per cent) with no difference between the two extravascular administrations (Frel 0.95 ± 10 per cent, intramuscular vs oral). After intramuscular administration tenoxicam was more rapidly absorbed compared to the oral dose (Tmax 0.71 h ± 80 per cent vs 1.4 h ± 62 per cent; p>0.05). Peak concentrations after oral and intramuscular administration (Cmax 2.5 mg 1−1 ± 19 per cent vs 2.7 mg l−1 14 per cent; p <0.05) were very similar.
Stereospecific evaluation of sotalol pharmacokinetics in a rat model: Evidence suggesting an enantiomeric interaction
Authors: Carr R. A. , Pasutto F. M. , Foster R. T.
Published: October 2006

Sotalol (STL) is a chiral β‐adrenergic blocking drug, which is useful clinically as the racemate in treating hypertension, and is also useful as a class III antiarrhythmic when administered as the pure S‐enantiomer. Utilizing a stereospecific high‐performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of STL is reported after administration of racemate and both pure enantiomers to a rat model. After administration of the racemate, enantiomers of STL had similar plasma concentration‐time profiles. Following administration of the pure S‐enantiomer of STL, however, systemic clearance was significantly reduced; R‐STL disposition after pure enantiomer administration was not significantly altered. Changes in systemic clearance of S‐STL after either racemate or enantiomer dosing were explained by corresponding changes in renal clearance. Renal clearance values of S‐STL were significantly reduced from 33·7 ± 6·0 to 28·9 ± 5·6 ml min−1 kg−1 for administration as racemate and pure enantiomer, respectively. As clearance of STL approximates reported values of renal blood flow, renal perfusion changes caused by the β‐blocking effects of R‐STL may explain changes in S‐STL disposition. It is suggested that dosing of STL as either racemate or pure enantiomer, depending on the clinical indication for use, may result in significantly altered enantiomer disposition.
Intestinal absorption pathway of γ‐aminobutyric acid in rat small intestine
Authors: Nácher A. , Polache A. , Moll‐Navarro M. J. , Plá‐Delfina J. M. , Merino M.
Published: October 2006

Intestinal absorption of γ‐aminobutyric acid (GABA), as a model compound for γ‐aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of β‐alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests to in vivo physiological conditions, a rat jejunum in situ study was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They show that the intestinal absorption of the γ‐aminoacid can be apparently described as a specialized transport mechanism which obeys Michaelis‐Menten and first‐order kinetics. Parameter values found were Vm = 13.99 ± 2.37 mM h−1, Km = 3.87 ± 0.63 mM, and ka(passive) = 0.362 ± 0.120 h−1. Through the perfusion of 5 mM β‐alanine solutions containing variable concentrations of GABA (from 5 to 50 mM), a partially competitive inhibition of β‐alanine absorption was apparently characterized.
Effects of benidipine hydrochloride (Coniel®), a new calcium antagonist, on the cardiac output, regional blood flow and vascular resistance in conscious, spontaneously hypertensive rats
Authors: Harashima Hideyoshi , Kiwada Hiroshi , Kajita Jirou , Kobayashi Satoshi
Published: October 2006

Benidipine hydrochloride is a calcium antagonist with a 1,4‐dihydropyridine derivative structure, and exhibits long‐lasting antihypertensive effects by inhibiting the voltagedependent Ca2+ channels. This study was undertaken to examine the effect of benidipine on central haemodynamics and regional blood flow (RBF) after intravenous administration of benidipine in conscious, spontaneously hypertensive rats. The microsphere method was used to measure cardiac output and RBF before and after the drug administration, using microspheres labelled with 57Co and 51Cr. Thirty minutes after the intravenous administration of benidipine (3 μg kg−1), the mean arterial pressure fell by 15% without significantly increasing the heart rate. The cardiac output increased by 41% and the systemic resistance decreased by 39%. Benidipine significantly increased RBF by 37,35, and 22% in kidney, heart, and small intestine, respectively, and decreased vascular resistance by 38, 38, and 32%, respectively. We concluded that benidipine reduced blood pressure by increasing RBF in the kidney and heart, while keeping RBF in other organs at a normal level. These results will provide a fundamental basis in support of the clinical benefits of benidipine for hypertensive patients, particularly those with renal failure.
The effect of colestipol and cholestyramine on ibuprofen bioavailability in man
Authors: Al‐Meshal Mohamed A. , El‐Sayed Yousry M. , Al‐Balla Sulaiman R. , Gouda M. Wafik
Published: October 2006

The purpose of this study was to determine whether a concomitant single oral dose of one of the anion exchange resins colestipol hydrochloride (10 g) or cholestyramine (8 g) administered with ibuprofen (400 mg) would alter the bioavailability of this non‐steroidal anti‐inflammatory agent. The study was performed according to a randomized three‐way crossover design in six healthy male volunteers. After dosing, serial blood samples were collected for a period of 10 h. Plasma harvested from blood was analysed for ibuprofen by a sensitive high‐performance liquid chromatographic method. There were no significant differences between colestipol treatment and control for peak plasma concentration (Cmax), time to peak concentration (Tmax), area under the plasma concentration—time curve (AUC), mean residence time (MRT), elimination rate constant (Kel), or elimination half‐life (t1/2). Cholestyramine treatment resulted in a significant decrease in AUC (26%, p< 0.05) and Cmax (34.4%, p <0.01) and a significant increase in Tmax (80%, p < 0.01) and MRT (20.2%, p < 0.05). Cholestyramine administration showed no significant effect on the Kel and t1/2 values. A significant correlation was obtained between the increase in MRT and the increase in Tmax. The confidence intervals (90%) of the mean values of the pharmacokinetic parameters (AUCO–∞ and Cmax) for the colestipol : control ratio were well within the acceptable range of 100 ± 20, whereas those for the cholestyramine : control ratio were outside it. Colestipol treatment was found to be bioequivalent to the control treatment by Schuirmann's two one‐sided t tests, while cholestyramine treatment was found to be bioinequivalent. The results indicate a lack of interaction between ibuprofen and colestipol and a potential significant interaction (decrease in rate and extent of absorption of ibuprofen) between cholestyramine and ibuprofen in patients receiving concurrent therapy.
Bioequivalence of pyrantel pamoate dosage forms in healthy human subjects
Authors: Fasanmade Adedigbo A. , Akanni Abraham O. , Olaniyi Ajibola A. , Fasanmade Adesoji A. , Tayo Fola
Published: October 2006

Drugs that are largely restricted to the gastro‐intestinal tract (GIT) for their therapeutic efficacy and that are not substantially absorbed into the body are usually inadequately studied in terms of systemic bioavailability. The possibility of systemic effects requires that bioavailabilities be studied to ensure against enhanced toxicity resulting from formulation differences. Pyrantel pamoate falls into this category. High‐performance liquid chromatography was employed in this study to determine plasma levels of pyrantel in nine healthy human subjects after administration of tablet and suspension dosage forms. Mean peak plasma concentrations of 37.56 ± 9.37, 35.89 ± 8.94, and 36.22 ± 10.10 ng mL−1 were obtained following administration of 750 mg pyrantel pamoate in three different formulations. The mean tmax values were 2.02 ± 0.12, 2.05 ± 0.356, and 2.05 ± 0.339 h respectively for the above dosage forms; the respective AUC0–9 values were 81.01 ± 12.97, 94.59 ± 17.18, and 101.47 ± 19.59 h ng mL−1. There was no statistically significant difference between the bioavailabilities of the dosage forms tested. Large inter‐subject variations were observed. One subject experienced abdominal discomfort and one experienced dizziness. It was not possible to clearly correlate individual variations in absorption with the observed adverse effect because the number of incidents was low (two out of 27 treatments).