bluuebunny/crossref_metadata_2025 huggingface dataset:
Genotype–phenotype correlations in cerebral cavernous malformations patients
Authors: Denier Christian , Labauge Pierre , Bergametti Françoise , Marchelli Florence , Riant Florence , Arnoult Minh , Maciazek Jacqueline , Vicaut Eric , Brunereau Laurent , Tournier‐Lasserve Elisabeth
Published: October 2006

Objective

To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers.

Methods

A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families was performed.

Results

A deleterious mutation was detected in 128 probands. Three hundred thirty‐three mutation carriers were identified (238 CCM1, 67 CCM2, and 28 CCM3). Ninety‐four percent of the probands with an affected relative had a mutation compared with 57% of the probands with multiple lesions but no affected relative (p < 0.001). The number of affected individuals per family was lower in CCM3 families (p < 0.05). The proportion of patients with onset of symptoms before 15 years of age was higher in the CCM3 group (p < 0.0025). Cerebral hemorrhage was the most common initial presentation in CCM3 patients. The average number of T2‐weighted imaging lesions was similar in the three groups, in contrast with a significantly lower number of gradient‐echo sequence lesions in CCM2 patients (p < 0.05). The number of gradient‐echo sequence lesions increased more rapidly with age in CCM1 than in CCM2 patients (p < 0.05).

Interpretation

Despite similarities among the three groups, there is a significantly lower number of affected individuals in CCM3 pedigrees, CCM3 mutations may confer a higher risk for cerebral hemorrhage, particularly during childhood, and the increment of gradient‐echo sequence lesions with age differs between CCM1 and CCM2 patients. Ann Neurol 2006
Simultaneous determination of methenamine and formaldehyde in the urine of humans after methenamine administration
Authors: Gollamudi Ramachander , Meyer Marvin C. , Straughn Arthur B.
Published: October 2006

Methenamine (hexamethylenetetramine) and its hydrolysis product formaldehyde are determined in the presence of each other in urine by a spectrophotometric method. Formaldehyde is assayed by a colour reaction with tryptophan, sulphuric acid and ferric chloride after precipitating methenamine by three treatments with mercuric chloride. Methenamine is indirectly analysed by hydrolysis to formaldehyde with dilute hydrochloric acid. Formaldehyde levels as low as 5·0 μg ml−1 in the presence of methenamine concentrations as high as 2·5 mg ml−1 can be assayed. Of practical significance is the feature that urine may be stored up to 1 week for analysis, by appropriate dilution and freezing, without excessive loss of methenamine or formaldehyde. The method was applied to the determination of the bioavailability of methenamine hippurate in ten human volunteers.
Animal model for investigation of fluphenazine kinetics after administration of long‐acting esters
Authors: Altamura A. C. , Whelpton R. , Curry S. H.
Published: October 2006

A model was developed for studying fluphenazine availability and disposition. Rats were given doses of radioactively labelled esters of fluphenazine by intramuscular injection. Radioactivity excreted in urine, faeces, and expired air was assessed for fluphenazine esters, fluphenazine, and CO2 content. Levels of fluphenazine and its esters were measured in plasma, brain, and muscle (injected and non‐injected samples). The data mimicked those obtained in other studies involving the same material given to human subjects, and posed new questions concerning the factors controlling fluphenazine availability when given as ‘long‐acting’ intramuscular injections.
Rapid fluorimetric procedure for the analysis of Fendosal in plasma and data following oral dosing
Authors: Hill H. M. , Chamberlain J. , Hajdu P. , Damm D.
Published: October 2006

A simple, rapid, and sensitive procedure is described for the determination of Fendosal in plasma. After extraction of Fendosal from buffered plasma, the drug is determined by measurement of the fluorescence induced by irradiation with short‐wave ultra‐violet (UV) light. The complete procedure can be completed in less than 2 h; one technician can perform up to 50 assays in one working day. The limit of detection corresponds to 0–1 μg ml−1 plasma. Drug concentration and induced fluorescence were linearly related over the concentration range 0–8 μg ml−1.
Disposition kinetics of disopyramide in patients with renal insufficiency
Authors: Shen Danny D. , Cunningham John L. , Shudo Isami , Azarnoff Daniel L.
Published: October 2006

The pharmacokinetics of an intravenous injection of disopyramide was studied in five normal subjects and six patients with varying degrees of renal impairment. The elimination rate constant (β) was related to the endogenous creatinine clearance (Clcr). However, a decrease in β was not observed until the Clcr was reduced below 40 ml min−1. Below 40 ml min−1 a linear relationship existed between β and Clcr. Similarly, the plasma elimination half‐life (t½β) showed a significant increase when the Clcr was less than 30 ml min−1. Hence, dosage modification for disopyramide is necessary only when renal function is severely impaired. Overall, the apparent volume of distribution in patients with renal insufficiency was reduced to two‐thirds of that in normal subjects. Therefore, in patients with Clcr less than 40 ml min−1 both the loading and maintenance dose of disopyramide should be reduced.
Relative bioavailability of three commercial quinidine dosage forms
Authors: Sirois Gerard , Eshaque Mohammad , Chabot Michel
Published: October 2006

Bioavailabilities of three quinidine formulations were compared. Two tablets of each dosage form were administered to 12 healthy volunteers according to a repeated Latin square design; plasma levels of unchanged and total drug were determined. Quinidine was absorbed significantly more rapidly from one of the formulations than the other two; the bioavailability of this formulation, calculated from intact drug data, normalized for subject differences, was also significantly greater than that of the other two, 68 and 76 per cent respectively. Individual comparisons of area under the curve (AUC) indicated that estimated relative bioavailability depends on the specificity of the assay, the adjustment of the AUC for the area beyond the last measurable plasma concentration and the normalization of the AUC. The data suggest there is a correlation between dissolution rate and peak plasma concentration.
Pharmacokinetic characteristics of ketoprofen suppositories
Authors: Caillé G. , Besner J. G. , Lacasse Y. , Vézina M.
Published: October 2006

The pharmacokinetic profile of ketoprofen suppositories following single and chronic (32 doses) administration to 12 healthy adult male volunteers was established. Each subject received a single rectal dose of 100 mg of ketoprofen on day 1, followed by one suppository of 100 mg b.i.d. for days 8–22, and finally one suppository on day 23. Plasma samples were analysed by gas‐liquid chromatography. Following single doses, the mean maximum observed concentrations of ketoprofen in plasma (6·56 μg ml−1) were achieved at 1·1 h; the mean elimination half‐life was 1·78 h. The results indicate that ketoprofen is rapidly and reproducibly absorbed and eliminated from the suppository dose form.
Isoniazid‐induced intolerance to ethanol in rabbit, guinea pig and rat
Authors: Whitehouse L. W. , Paul C. J. , Thomas B. H.
Published: October 2006

Isoniazid (50 or 100 mg kg−l p.o.) inhibited the elimination of ethanol (0·5, 1·0, and 2·5 g kg−l p.o.) from the plasma of rabbit, guinea pig, and rat. The effect of isoniazid, isonicotinic acid, N‐acetylisoniazid, N‐acetylhydrazine, N,N‐diacetylhydrazine, and hydrazine on the in vitro metabolism of alcohol by rabbit liver alcohol dehydrogenase was examined. Only isoniazid, hydrazine, and acetylisoniazid showed significant inhibitory activity with I50's of 17·7, 1·25, and 0·78 mmol 1−1 respectively. Intolerance to ethanol following isoniazid treatment was attributed to isoniazid inhibition of liver alcohol dehydrogenase.
Pharmacokinetics of drugs in blood I. Unusual distribution of gentamicin
Authors: Lee Myung G. , Chen Mei‐Ling , Huang Shiew‐Mei , Chiou Win L.
Published: October 2006

Distribution kinetics of gentamicin in whole blood were studied. After spiking human blood to an initial concentration of 20 μg ml−1, plasma gentamicin concentrations dropped to minima at about 5 min then increased to maxima at about 15 min and remained constant afterwards. A difference of up to 36 per cent between the maximum and minimum was found. The equilibration was faster with lower initial concentrations. These unusual distribution phenomena might be attributed to the Schiff base formation between nonprotonated amino groups of gentamicin and free fatty aldehyde groups on blood cell membrane. The mean equilibrium blood cells/plasma partition ratio was about 0.1. Similar equilibration kinetics were observed with blood of rabbits after being intravenously dosed with gentamicin. Therefore, the time elapsed between the collection and centrifugation of blood samples, especially shortly after dosing, may have a significant effect on the ‘measured’ plasma gentamicin concentration. Distribution between plasma and blood cells may also occur in a similar manner with other drugs which have primary amino groups. It is recommended that distribution kinetics of drugs and metabolites in blood be included in pharmacokinetic studies.
Rectal infusion of the model drug antipyrine with an osmotic delivery system
Authors: De Leede L. G. J. , De Boer A. G. , Breimer D. D.
Published: October 2006

An osmotically‐powered rectal drug delivery system, was used for the rectal infusion of the model drug antipyrine. The system, which is slightly larger than a normal suppository, has a nominal pumping rate of 43 μl h− 1 over at least 30 h. Four healthy volunteers kept two such systems in their rectum for a sum total of 98 h. Saliva and plasma concentrations were determined at regular intervals and in all cases a very constant steady‐state saliva and plasma concentration was reached and maintained. Defecation and reinsertion of the drug delivery system did not cause any irregularities in the concentration profile. The system was very well tolerated by the volunteers.
Platinum levels in human erythrocytes following intravenous administration of cisplatin: Importance of erythrocytes as a distribution site for platinum species
Authors: Long D. F. , Patton T. F. , Repta A. J.
Published: October 2006

Recent reports of the extent of uptake of cisplatin and possible biotransformation products of cisplatin by red blood cells of humans receiving this drug have been conflicting. In vitro and in vivo studies of the platinum content of washed red blood cells following exposure to cisplatin have been conducted. Low levels of platinum were found in the red cell lysate of the erythrocytes of humans receiving cisplatin. The platinum was primarily associated with red cell lysate and little, if any, platinum appeared to be associated with the cell membrane. The in vivo studies indicated that the intracellular platinum levels are rapidly achieved following cisplatin administration and the platinum concentration appears to be linearly related to the administered dose. However, the fraction of platinum found within the erythrocytes is slight, representing only about 1 per cent of the administered dose. In light of the reactivity of cisplatin with compounds containing divalent sulphur and the millimolar glutathione levels present within erythrocytes, it is unlikely that the platinum released from the red blood cell is in the form of cisplatin. Therefore, it is doubtful that the red blood cell is a major site for cisplatin distribution and the anticancer activity of the platinum released from red blood cells is questionable.
Bioavailability in man of atenolol and chlorthalidone from a combination formulation
Authors: McAinsh James , Bastain William , Young Jean , Harry John D.
Published: October 2006

In this comparative bioavailability study in 12 healthy volunteers the blood level profiles and urinary recoveries of both atenolol and chlorthalidone were studied following the administration of the drug as a fixed combination (‘Tenoretic’), as a free combination, and individually, at doses of 100 mg atenolol, and 25 mg chlorthalidone.

There were no statistically significant differences between the three formulations of atenolol in terms of individual blood levels, half‐life, area‐under‐the‐curve, and urinary excretion. The half‐lives were between 5 and 6 h in agreement with other published data. Thus the bioavailability of atenolol from the fixed combination is equivalent to that from the free combination and from the atenolol tablet.

The chlorthalidone blood levels were slightly higher following the administration of the fixed combination when compared with the free combination or the chlorthalidone tablet. This observation was reflected in estimates of the area under the curves and the urinary recoveries. The half‐lives of all three formulations were similar at about 60 h.

It is concluded that combining chlorthalidone and atenolol in a single tablet does not reduce the systemic bioavailability of either component.
Bioavailability of terfenadine in man
Authors: Okerholm R. A. , Weiner D. L. , Hook R. H. , Walker B. J. , Leeson G. A. , Biedenbach S. A. , Cawein M. J. , Dusebout T. D. , Wright G. J. , Myers Mary , Schindler Valerie , Cook C. E.
Published: October 2006

Fourteen normal male subjects were given either 60 mg or 180mg of terfenadine suspension in a randomized two‐way crossover study. Peak plasma concentrations of 1.544 ± 0.726 (mean ± S.D.) ng ml−1 were obtained in 0.786 ± 0.426 h following the 60 mg dose and displayed an AUC of 11.864 ± 3.369 ng h ml−1. Whereas peak plasma concentrations of 4.519.2 ± 002ng ml−1in 1.071 ± 0.514h were obtained following the 180mg dose. The AUC following the 180 mg dose was 44.341 ± 22.041 ng h ml−1. When 60 mg of 14C terfenadine was given to six additional subjects, the peak plasma concentrations of 351.43ng equivalents per ml were obtained in 1.67 ± 0.41 h and the AUC was 2297.71 ± 310.85ng‐equivalentshml−1. This indicates that approximately 99.5 per cent of the terfenadine related material that is absorbed undergoes biotransformation. Urinary excretion of 14C accounted for 39.89 ± 5.29 per cent of the dose while 60.58 ± 2.44 per cent of the dose was recovered in the feces in twelve days. Thin‐layer chromatographic (TLC) examination of fecal extracts showed only a trace of material chromatographing with terfenadine. This may indicate that the 14C present in the feces is not due to lack of absorption.
Interrelation between plasma protein binding, rate of injection and the anesthetic effect of thiopental
Authors: Kurz H. , Fichtl B.
Published: October 2006

Following thiopental injection to rabbits in doses of 5 mg kg−1 intravenously (i.v.) the sleeping time lasted longer after injection by bolus than after administration made more slowly over 30 or 60 s, respectively.

Peak concentration in the blood of the animals after bolus injection was about four times higher than after slow injection.

The determination of protein binding showed that the unbound fraction of thiopental at the high concentration following bolus injection is almost doubled compared with the unbound concentration following the slow injections. Therefore it is concluded that this contributes to an increased concentration of thiopental in the brain during the initial phase of distribution thus extending the sleeping time.

The results from experiments using a distribution model give additional evidence supporting this conception.
Normal pharmacokinetics of 99mTc‐diphosphonate after intravenous administration
Authors: Castronovo Frank P.
Published: October 2006

In the past several years bone imaging has become a routine diagnostic tool for the nuclear medicine clinician. However, increased information may be derived by determinating the radio‐pharmacokinetic parameters associated with blood, urine, and bone. In an adult male population of normals (N = 5–6) blood clearance, urinary excretion, and skeletal uptake of 99mTc‐Diphosphonate were determined as a function of time after intravenous (i.v.) administration. The quantitative imaging studies (lower lumbar region) were performed up to 1 h post administration with a scintillation camera interfaced to a computer. Blood levels exhibited a triexponential clearance pattern and urinary excretion of the radiopharmaceutical was essentially complete by 4 h. The computer‐generated images showed an initial early uptake in bone, kidneys, and soft tissue. Thereafter, a parallel fall‐off in activity was observed in kidneys and soft tissue, with a concomitant increase in bone.
A comparison of intravenous and subarachnoid lidocaine pharmacokinetics in the rhesus monkey
Authors: Denson Donald D. , Ritschel Wolfgang A. , Turner Patricia A. , Ohlweiler David F. , Bridenbaugh Phillip O.
Published: October 2006

A comparative study between intravenous and subarachnoid lidocaine in the rhesus monkey was conducted in an effort to compare the kinetics of lidocaine in the monkey with reported intravenous human data, and to determine the rate and extent of systemic absorption of lidocaine following subarachnoid injection. Each animal received an intravenous and subarachnoid treatment in an effort to determine the fraction of drug absorbed. Pharmacokinetic parameters were calculated for each animal based on arterial blood concentrations of lidocaine. In the case of the intravenous data, a standard two‐ compartment model was used. Subarachnoid injections were evaluated by fitting data to an extravascular one‐compartment model and by analog computer fitting of the blood level data to an extravascular two‐compartment model. Data for both intravenous and subarachnoid injection were also analysed independent of compartment model.
Blood levels following multiple oral dosing of chlorpheniramine conventional and controlled release preparations
Authors: Vallner J. J. , Kotzan J. A. , Stewart J. T. , Brown W. J. , Honigberg I. L. , Needham T. E. , Dighe S. V.
Published: October 2006

An examination of steady‐state performance of chlorpheniramine conventional versus controlled release products was conducted using 15 male subjects in a 3‐way crossover study with a 2‐week washout period between studies. The study was designed to determine if chlorpheniramine formulations provide consistent pharmacokinetic performance between individual units upon going from single dose to multiple dose therapy. In addition, the validity of predicting steady‐state levels for these kinds of products using only single oral dose data was examined. The dosage forms evaluated were a conventional 4mg tablet, and 8 mg barrier coated‐bead capsule, and an 8 mg repeat action tablet. Multiple doses of each product were orally administered to each subject for 6 days prior to the study day to achieve steady‐state levels and on the actual study day. Serum samples were collected at specific time intervals on the study day, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two‐compartment open model. The mean plasma elimination half‐lives of the various dosage forms were in the range 24.5–25.4h. There was no rapid release of drug from the controlled release products nor did they have drug release problems during the dosing interval. Good agreement was obtained between predicted average drug concentration at steady‐state and drug concentration actually present for all the formulations studied. Based upon comparative examination of AUC, Cmax, and fraction of dose absorbed data, the controlled release products administered every 12h were comparable in performance to a conventional release tablet administered every 6 h. Since the half‐life of chlorpheniramine is approximately 1 day, therapeutic management may possibly be gained with dosing the patient once daily with a controlled release product or twice daily with a conventional tablet.
The relative bioavailability of a commercial propranolol hydrochloride tablet in man
Authors: Roscoe R. , Cooper J. , Wilson T. W. , Joshi N. N. , Midha K. K.
Published: October 2006

A relative bioavailability study of a conventional tablet of propranolol hydrochloride was conducted in a group of 18 healthy volunteers employing the innovator's product as the reference tablet formulation. Based on plasma levels of propranolol for the 24 h following administration of 2 ± 40 mg oral propranolol hydrochloride tablets, the relative extent of bioavailability was shown to be 100.8 per cent for the test tablet formulation; no significant differences were detected between formulations with respect to any of the pharmacokinetic parameters examined. Large intersubject variations in plasma propranolol concentrations and the subsequently calculated areas under the plasma concentration/time curves were attributed to substantial presystemic biotransformation differences.
Age‐related differences in ophthalmic drug disposition II: Drug‐protein interactions of pilocarpine and chloramphenicol
Authors: Miller Susan C. , Patton Thomas F.
Published: October 2006

Although drug‐protein interactions have been shown to be important in the transport of drugs into and through the eye, age‐related differences in ocular drug‐protein binding have not been explored. This study was designed to investigate protein binding characteristics of pilocarpine and chloramphenicol in aqueous humour and plasma from rabbits of different ages. The method of equilibrium dialysis was used to quantitate drug‐protein interactions. Younger animals showed decreased binding of chloramphenicol in plasma when compared to older rabbits. On the other hand, the interactions of both drugs with aqueous humour proteins were more extensive in younger rabbits. Age‐related differences in drug‐protein binding were not directly related to the total protein contents of the respective biological fluids. These findings suggest possible age‐related differences in the relative protein fractions contained in aqueous humour and plasma, or qualitative differences in the binding capacity of the proteins involved.
The single‐point method of dosage prediction: Pharmacokinetic basis and method optimization
Authors: Love B. L. , Tsuei S. E. , Thomas J. , Nation R. L.
Published: October 2006

Based on the principle of superposition an expression has been established relating a drug concentration at steady‐state to a concentration after a single dose. This relationship applies for drugs with linear pharmacokinetics given at equal dosage intervals and it is independent of the route of administration. The relationship provides theoretical justification for the single‐point method of dosage prediction reported in the literature. The test conditions in the method can therefore be optimized and the limits of the method defined. The expression can also be used for individualized prediction of maintenance dose after estimation of drug half‐life in the patient with no limit to half‐life values to which it can be applied.
Comparative bioavailability and pharmacokinetics of hydrochlorothiazide from oral tablet dosage forms, determined by plasma level and urinary excretion methods
Authors: Barbhaiya R. H. , Patel R. B. , Corrick‐West H. P. , Joslin R. S. , Welling P. G.
Published: October 2006

The bioavailability and pharmacokinetics of two hydrochlorothiazide products were compared following single 50 mg oral doses to 20 healthy male volunteers. Plasma and urine were assayed for hydrochlorothiazide by a specific and sensitive HPLC method. Plasma profiles of hydrochlorothiazide were adequately described by a triexponential function. The bioavailability of hydrochlorothiazide from the two brands did not differ significantly as judged by the values of Cmax, tmax, AUC0→x, mean residence time, variance of residence time, and urinary excretion of unchanged drug. Close similarity was observed between urinary excretion rates and concentrations of drug in plasma.
Drug and metabolite concentrations combined in predicting steady‐state concentrations from test doses
Authors: DeVane C. Lindsay , Jusko William J.
Published: October 2006

The first day test dose versus steady‐state relationship for predicting drug doses was evaluated for the situation where metabolites are produced. An organ clearance model incorporated into a digital computer program simulated drug and metabolite disposition. When the terminal elimination rate for metabolite was similar to that of its precursor, the drug and metabolite concentrations could be summed for use in test dose predictions as the resulting accumulation ratios were similar. However, if an active metabolite is eliminated more slowly than its precursor, future studies should consider these concentrations separately for predictive purposes. The theoretical results agreed with concentration data obtained from a study of patients who took imipramine.
Influence of inflammatory disease on the clinical pharmacokinetics of atenolol and metoprolol
Authors: Kirch Wilhelm , Spahn Hilde , Ohnhaus Edgar E. , Köhler Hans , Heinz Ute , Mutschler Ernst
Published: October 2006

The influence of inflammatory disease on the pharmacokinetics of atenolol and metoprolol was investigated after administering single oral 100mg doses of the drugs to six subjects. Each subject had a respiratory tract infection with an erythrocyte sedimentation rate (ESR) of over 20 mm in the first hour and a body temperature of at least 38·5°. Since the subjects subsequently received atenolol and metoprolol when they were healthy, each person acted as his own control.

Inflammatory disease had no influence on the kinetics of metoprolol. In contrast, mean peak plasma levels and AUC for atenolol were significantly lower, both by about 40 per cent, during infectious disease compared to the healthy state (p<0·05), where as renal clearance of atenolol slightly increased from 110·8 ± 14·7mlmin−1 in the healthy state to 128·21·6mlmin−1, when the ESR's were elevated. The elimination half‐life of atenolol, about 10 h, was not affected by the health status of the subjects. Reduced absorption in the gastro‐intestinal tract and enhanced elimination of atenolol from plasma might account for the decreased AUC and peak plasma levels of the drug during inflammatory disease.
Absorption and disposition characteristics of nitrofurantoin in dogs
Authors: Niazi S. , Vishnupad K. S. , Veng‐Pedersen P.
Published: October 2006

This study reports the disposition kinetic properties of nitrofurantoin in dogs following single intravenous and oral administration of various formulations of nitrofurantoin. Also reported here is the effect of delaying gastric emptying by food and atropine on the absorption characteristics of nitrofurantoin. The drug absorption parameters calculated using a deconvolution computer program indicate that the rate and extent of enterohepatic recycling affects the elimination and absorption rate constants and thus confound the bioavailability calculations of nitrofurantoin, heretofore unrecognized in the literature.

The plasma half‐life following intravenous administration was 31 min (monoexponential equation) with little effect of enterohepatic recycling noted. Following oral administration, a biexponential equation with lag‐time was used to fit the blood levels. The absorption half‐lives were higher when nitrofurantoin was administered as a solid dosage form compared to a solution. The absorption half‐lives following tablet administration ranged from 30 to 72 min and were not affected by food or atropine. The elimination half‐lives following oral administration ranged from 19 to 87 min with significantly prolonged elimination when solid dosage forms were administered compared to solution. The extent of absorption ranged from 38 to 120 per cent. A direct correlation between the absorption and elimination half‐lives was established, indicating that increased biliary recycling direct affects the apparent disposition half‐life. The three brands of nitrofurantoin tested for bioavailability showed that the use of blood levels without appropriate corrections for biliary recycling are not suitable for bioavailability testing of nitrofurantoin. The use of urinary excretion data in evaluating nitrofurantoin bioavailability is also questioned in the study.
Systemic bioavailability and pharmacokinetics of methylprednisolone in patients with rheumatoid arthritis following ‘high‐dose’ pulse administration
Authors: Narang P. K. , Wilder R. , Chatterji D. C. , Yeager R. L. , Gallelli J. F.
Published: October 2006

The absolute and relative bioavailability of two methylprednisolone formulations (capsules and suspension) was determined along with its pharmacokinetics in four arthritic female patients, following an unconventional high‐dose pulse of 1 g. Plasma concentrations of the drug were measured by a sensitive and specific high‐performance liquid chromatographic (HPLC) procedure. The disposition of methylprednisolone from plasma following intravenous (i.v.) infusion of its succinate ester appeared monoexponential with a mean half‐life of 2·4 h and an apparent volume of distribution (Vd) of 50 1 (0·871 /kg). The total body clearance (Cl) averaged 15·121/h. Absolute bioavailability was assessed by comparing the areas under the plasma concentration time curves (normalized to dose) following oral administration of capsule or suspension with those of intravenous administration. No significant difference (p > 0·2) was observed when systemic availability (f, expressed in per cent) following administration of drug in capsule (f = 49·35 per cent) was compared with that obtained following the administration of drug in a suspension (f = 58·26 per cent). The difference in the observed and predicted f may be due to incomplete absorption, hepatic and/or extrahepatic metabolism of methylprednisolone. Subjective evaluation showed no side effects of this high‐dose pulse therapy in any of the patients.
Biliary secretion of sulindac and metabolites in man
Authors: Dobrinska M. R. , Furst D. E. , Spiegel T. , Vincek W. C. , Tompkins R. , Duggan D. E. , Davies R. O. , Paulus H. E.
Published: October 2006

The biliary secretion of sulindac and metabolites after a single 400 mg oral dose of the drug was studied in 3 elective gallbladder surgical patients following placement of an occludable T‐tube in the common bile duct. Bile and systemic plasma were sampled at frequent intervals for up to 36 h postdose. The apparent biliary clearance (V̇cl,bilc) of the prodrug sulindac is about 25 times greater than that of the pharmacologically active sulfide metabolite. The total biliary flux of drug in normal man with an uninterrupted enterohepatic cycle, calculated from V̇cl,bile and historic mean plasma drug AUC values, averages 144 and 12·2 per cent of the dose as sulindac and the sulfide metabolite, respectively. Thus, enterohepatic recycling of the drug in man is principally in the form of the prodrug which not only limits exposure of the intestine to the active moiety but also sustains systemic concentrations of active drug upon reabsorption of the prodrug.
A new metabolite of butylated hydroxyanisole in man
Authors: El‐Rashidy Ragab , Niazi Sarfaraz
Published: October 2006

Butylated hydroxyanisole (I) is one of the most commonly used food antioxidants. Its use has been suggested to inhibit a variety of carcinogenic responses. The present study on the disposition kinetics of (I) in man indicates that contrary to previous reports, (I) undergoes significant O‐demethylation in the body yielding a tert‐butyl hydroquinone. It is suggested that this metabolic conversion may be responsible for some of the in vivo activities of (I) against chemical carcinogens.
The influence of vitamin C on antipyrine pharmacokinetics in elderly men
Authors: Blanchard James , Achari Ramanuj , Harrison Gail G. , Conrad Kenneth A.
Published: October 2006

The influence of vitamin C on the pharmacokinetics of antipyrine was investigated in eleven elderly men aged 65–74. Antipyrine (15 mg kg−1) was administered intravenously on three separate occasions over a 7‐week period: (a) before dietary vitamin C restriction, (b) after approximately 5 weeks of dietary vitamin C restriction, and (c) after 2 weeks of vitamin C supplementation (500 mg orally twice daily). The mean plasma and leucocyte vitamin C levels (±S.D.) before vitamin C restriction were 1·26 ± 0·31 mg dl−1 and 26·6 ± 6·7 μg 10−8 leucocytes, respectively. These values decreased and then increased significantly following vitamin C restriction and supplementation, respectively. The mean plasma half‐life of antipyrine was 10·2h and the mean plasma clearance was 2·561h−1 1·73 m−2 before vitamin C restriction. No significant changes in the clearance, volume of distribution, or half‐life of antipyrine occurred during the study, indicating that short‐term alterations in vitamin C intake do not affect the pharmacokinetics of antipyrine in elderly males.
Thiazides XI: Partitioning of chlorothiazide in red blood cells after oral administration
Authors: Shah Vinod P. , Walker Mark A. , Hunt John P. , Schuirmann Donald , Prasad Vadlamani K. , Cabana Bernard E.
Published: October 2006

Uptake of chlorothiazide by red blood cells after oral drug administration was investigated. Chlorothiazide was administered to normal healthy volunteers as a solution or a tablet. Frequent blood samples were collected and analysed by a specific HPLC method. The results indicate that there is a significant uptake of chlorothiazide by red blood cells, resulting in a higher blood AUC compared to plasma AUC.
Effect of using an incorrect elimination rate constant in application of the Wagner–Nelson method to theophylline data in cases of zero order absorption
Authors: Wagner John G.
Published: October 2006

Some authors have used an elimination rate constant derived from one theophylline treatment (e.g. the elixir) to apply the Wagner–Nelson method to concentration–time data from another treatment (e.g. a sustained‐release form). Since there is considerable intrasubject variation in the elimination rate constant of theophylline such a practice usually involves use of an incorrect rate constant. By means of theoretical treatment and simulations the effects of such a practice are shown and illustrated.
Apparent dose‐dependent oral absorption of cyclosporin a in rats
Authors: Ueda Clarence T. , Lemaire Michel , Gsell Guy , Misslin Pierrette , Nussbaumer Kurt
Published: October 2006

The oral absorption of cyclosporin A (CyA) was studied in rats after 6, 12, 18, and 23 mg kg−1 doses were given in an olive oil solution to determine if CyA absorption from the gastrointestinal tract was dose‐dependent. Using serial blood samples obtained at various times after the respective doses, analysis of the resultant blood CyA concentration–time curves suggested that the rate of CyA absorption for all four doses was an apparent zero‐order process. Moreover, the rate of CyA absorption appeared to be dose‐dependent, increasing as the dose of CyA increased. Similarly, the extent of CyA absorption (F) also exhibited dose‐dependent characteristics in this study. F is increased from 0·13 after the 6 mg kg−1 dose to 0·22 with the 18 and 23 mg kg−1 doses (p < 0·05). In the present investigation, the observed values for the duration of drug absorption (T), terminal first‐order rate constant (β) and corresponding elimination half‐life (T1/2β) of approximately 4–5 h, 0·030 h−1 and 21–28 h, respectively, were similar for all CyA doses. Moreover, no difference in β was observed after oral or intravenous drug administration. Absorption lag times of 1–2 h were found. The results suggested that the apparent dose‐dependent absorption of CyA observed in the present study was possibly related to the effects of olive oil on gastric emptying and that CyA might be unstable in the gastric fluids and/or metabolized by the gastric mucosa.
Biliary excretion and enterohepatic circulation of two beta‐adrenergic blocking drugs, exaprolol and propranolol in rats
Authors: Tomčíková O. , Bezek Š. , Ďurišová M. , Faberová V. , Zemánek M. , Trnovec T.
Published: October 2006

Plasma levels and excretion of two beta‐adrenoceptor blocking drugs 3H‐exaprolol and 3H‐propranolol wereobserved up to 96 h after a single i.v. administration to rats. Terminal half‐lives of 26·8 ± 9·1 h and 51·3 ± 7·5 h were found for exaprolol and propranolol, respectively. The recovery of 3H radioactivity in feces following i.v. administration of the drus (34·2 ± 0·8 per cent and 12·0 ± 1·3 per cent 3H of exaprolol and propranolol, respectively) is of biliary origin, as 30·7 ± 3.5 per cent and 13·4 ± 3.6 per cent 3H of exaprolol and propranolol, respectively, was excreted in the bile after i.v. administration. Enterohepatic circulation of the drugs was studied using the donor‐recipient rat method. After intraduodenal administration of donor bile to the recipient rat approximately 50 per cent and 40 per cent of the biliary 3H activity of exaprolol and propranolol, respectively, was re‐excreted following absorption. A formula for calculating the amount of the substance together with its metabolites excreted in the bile, urine or feces as a result of enterohepatic circulation has been proposed.
Comparison of the bioavailability of oral, rectal and intramuscular promethazine
Authors: Schwinghammer Terry L. , Juhl Randy P. , Dittert Lewis W. , Melethil Srikumaran K. , Kroboth Frank J. , Chungi Vinod S.
Published: October 2006

The bioavailabilities of generic and reference promethazine 50 mg rectal suppositories were compared with that of 50 mg reference oral solution (24 subjects), and all three treatments were compared with a 50 mg reference i.m. injection (six subjects). Plasma samples were assayed by an HPLC method with triflupromazine as the internal standard. Both suppositories produced lower peak plasma concentrations (Cmax) and longer times to peak concentration (Tmax) than did the oral solution. There were no significant differences in the mean area under the plasma concentration–time curves (AUC) from 0 to 24 h among the three treatments. The Cmax of the i.m. injection was significantly higher than the other three treatments, while the Tmax of the injection was significantly shorter than the reference suppository only. The mean AUC of the injection was significantly greater than the AUCs of the other three treatments. Rectal suppositories of promethazine are more slowly absorbed than oral solutions or i.m. injections; rectal suppositories and oral solutions are less bioavailable than i.m. injections. Diminished systemic bioavailability may result from extensive first‐pass hepatic metabolism that occurs after both oral and rectal dosing. There is a high degree of inter‐subject variation in the bioavailability of promethazine rectal suppositories and oral solutions.
Relationship between total body clearance of caffeine and urine flow rate in elderly men
Authors: Trang John M. , Blanchard James , Conrad Kenneth A. , Harrison Gail G.
Published: October 2006

The total body clearance (CL), renal clearance (CLR), and nonrenal clearance (CLNR) of caffeine from plasma were determined following the intravenous administration of caffeine (4mgkg−1) to ten healthy men (aged 66–86 years) on three separate occasions. Positive correlations were observed between CL and urine flow rate (UFR), between CLR and UFR, and between CLNR and UFR (r = 0.8947, p = 0.0002; r = 0.8832, p = 0.0003; and r = 0.8920, p = 0.0002, respectively). Previous studies have established similar relationships between CLR and UFR for caffeine and its initial dimethylxanthine metabolites; theophylline, theobromine, and paraxanthine. A relationship between CL and UFR has not been reported previously.
On pharmacokinetics in target tissues
Authors: Weiss Michael
Published: October 2006

Based on a two‐compartment organ model the total exposure in a target tissue, the mean tissue residence time and the peak time of the tissue concentration are evaluated in terms of tissue to blood partition coefficient and permeability coefficient (membrane permeability) of the drug, as well as the organ volume and blood flow. The total exposure is dependent upon the partition coefficient whereas the mean residence time is also affected by the permeability coefficient of the target organ. The peak time of tissue concentration following bolus intravenous injection appears to be mainly determined by the mean organ transit time and the time course of blood concentration. A tissue specific therapeutic ratio is defined using the concept of total exposure and the advantages of a local route of drug administration are discussed in this respect.
Bioavailability studies with ciglitazone in beagles I. Effect of a meal on the bioavailability of three ciglitazone dosage forms
Authors: Cox S. R. , Harrington E. L. , Hill R. A. , Capponi V. J. , Shah A. C.
Published: October 2006

Three separate Latin square crossover studies were conducted in beagles to examine the effect of a meal on the bioavailability of a ciglitazone tablet, suspension, and solution. In these studies, drug was administered to fasted animals with either 50ml water or with 180g Purina Dog Chow and 20g butter. The data indicated that the meal significantly increased the AUC by about 40 per cent for both the tablet and the suspension but had no significant effect on the solution treatment. Comparisons across studies indicated low bioavailability in fasted animals from either the tablet or suspension relative to the solution. When drug was co‐administered with a meal, however, bioavailability appeared to be independent of dosage form.
Adriamycin‐loaded albumin microspheres: Preparation, in vivo distribution and release in the rat
Authors: Willmott N. , Cummings J. , Stuart J. F. B. , Florence A. T.
Published: October 2006

Adriamycin‐loaded bovine albumin microspheres have been prepared by a technique that allows preparation and administration to animals on the same day. Criteria adopted for injection were that microspheres should be stable and of a size such as to become trapped in capillary beds. These conditions were fulfilled by preparing microspheres using glutaraldehyde concentrations greater than 0.5 per cent and the appropriate combination of stirring speed and continuous phase viscosity. After systemic administration rats were sacrificed at intervals and major visceral organs examined for entrapped microspheres and serum for released drug. Microspheres sieved out in the first capillary bed encountered, the lung, then following biodegradation they disappeared at rate dependent on the amount of cross‐linking agent used in their preparation. In contrast to bolus injection, serum drug levels after microsphere administration indicated an initial rapid release followed by a more protracted phase lasting at least 24 h. This latter observation is consistent with drug release during biodegradation of carrier.
Pharmacokinetics of furosemide after three different single oral doses
Authors: Waller Elaine S. , Massarella Joseph W. , Tomkiw Motria Sharanevych , Smith Robert V. , Doluisio James T.
Published: October 2006

Furosemide solution was orally administered to 21 healthy adult males to determine dose proportionality over the dose range used and the reproducibility of disposition following a repeated dose. Furosemide solution was given in doses of 20, 40, and 80mg, with the 40 mg dose repeated once. Blood was collected for 12 hours post‐dose and urine for 24 hours. The maximum plasma concentrations resulting from 20, 40, and 80mg doses were significantly different (p < 0.05). Dose normalized maximum concentrations for the 20 and 80 mg doses were significantly different (p < 0.05). Mean time to Cpmax was 50 minutes, with no differences observed among doses. Plasma AUCs were significantly different (p < 0.05) for 20, 40, and 80mg. Dose normalized AUCs were not significantly different. Mean amounts of furosemide in urine (Xu) were 9.62, 16.7, and 32.0 mg for the 20, 40, and 80 mg doses, respectively. These amounts were significantly different (p <0. 05); dose normalized amounts were not significantly different. Renal clearances of furosemide following the three doses were not significantly different. Regressions of Cpmax, AUC and Xu on dose were significant. There were no significant differences in Cpmax, tmax, AUC or Xu for 40 mg given on two separate days. Renal clearance of furosemide was statistically different for 40mg given on two separate days, but the difference was not clinically significant. The pharmacokinetics of furosemide are linear over the dosage range studied. Furosemide 40 mg given on two separate days results in similar disposition parameters.
The relationship between buspirone bioavailability and dose in healthy subjects
Authors: Gammans R. E. , Mayol R. F. , MacKenthun A. V. , Sokya L. F.
Published: October 2006

Dose dependency of the pharmacokinetics of buspirone, a new anxiolytic agent, was tested in 24 healthy volunteers. Each subject received 10, 20, and 40 mg doses according to a randomized, three‐way crossover design with a 7‐day interval between treatments. Buspirone AUC values at 10, 20, and 40 mg doses were in the ratio of 1:1.7:3.5 while Cmax values, had a ratio of 1:1.9:3.7. The dose normalized (10 mg basis) AUC and Cmax values, Tmax values, and half‐lives were not significantly different (p > 0.05) among the doses. Buspirone half‐life did not change as a function of dose (mg kg−1). It was concluded that buspirone exhibits linear pharmacokinetics following doses in the therapeutic range.
Pharmacokinetics and pharmacodynamics of bromocriptine in the rat
Authors: Schran H. F. , Tse F. L. S. , Bhuta S. I.
Published: October 2006

The absorption, distribution, and excretion of bromocriptine were studied following oral and parenteral administration of non‐radioactive and 14C‐labelled drug in the rat. Total radioactivity was measured in blood, tissues, and excreta by liquid scintillation counting while the parent drug was determined in plasma and selected tissues by radioimmunoassay. The pharmacokinetic observations were compared with the time course of drug‐induced hypothermia in cold‐room acclimatized rats. The results indicated that oral doses of bromocriptine were rapidly, though incompletely (32‐40 per cent), absorbed, but underwent extensive first‐pass metabolism, resulting in an absolute bioavailability of only 6 per cent. The bioavailability increased to approximately 22 per cent in rats pretreated with the hepatic microsome inhibitor proadifen, thus suggesting the liver as the principal site of biotransformation. Absorbed bromocriptine showed preferential distribution into the tissues, although no apparent accumulation of drug‐related material occurred in the body. The drug was eliminated almost exclusively by metabolism and biliary excretion into the faeces. Comparison of the pharmacodynamic and the pharmacokinetic profiles indicated a dose relationship between hypothermia and plasma bromocriptine concentrations but not total radioactivity levels. The hypothermic response was also intensified by proadifen pretreatment, thus confirming the parent drug as the pharmacologically active entity. It is believed that the previously reported delay in the onset of bromocriptine activity is not pharmacokinetic in nature, but is related to the properties of the receptors at the target site or to the pharmacologic events that result in the observed effects.