bluuebunny/crossref_metadata_2025 huggingface dataset:
No association between periconceptional multivitamin supplementation and risk of multiple congenital abnormalities: A population‐based case‐control study
Authors: Czeizel Andrew E. , Puhó Erzsébet H. , Bánhidy Ferenc
Published: October 2006

Two previous Hungarian intervention trials showed that periconceptional folic acid‐containing multivitamin supplementation did not change the total (birth + fetal) prevalence of cases with multiple congenital abnormalities (MCAs). However, two US observational studies found an elevated risk for MCAs in the offspring of women who reported periconceptional use of multivitamins containing folic acid. These conflicting results stimulated us to evaluate the data set of the Hungarian Case‐Control Surveillance of Congenital Abnormalities and to check the possible association between the use of periconceptional multivitamin supplementations and the total prevalence of cases with MCAs. Of 1,349 cases with MCA, 69 (5.1%) had mothers who used multivitamins during the second and third month of pregnancy. Of 2,405 matched controls without any defect, 126 (5.2%) had mothers who used multivitamin supplementation in early pregnancy. Of 21,494 malformed controls with isolated congenital abnormalities, 1,052 (4.9%) mothers received supplementation with multivitamins during the critical period of CAs including MCAs. There was no difference in the use of multivitamins among the study groups either in the total data set or at the evaluation of only prospective medically recorded data. Medically recorded folic acid use without any multivitamins in the second and third gestational month showed some protective effect for MCAs. In conclusion, our observational case‐control study did not detect a folic acid containing multivitamins during the early pregnancy as a risk factor for MCAs. © 2006 Wiley‐Liss, Inc.
Comparison of two dissolution apparatuses with correlation of in vitro‐in vivo data for prednisone and prednisolone tablets
Authors: Milsap Rebecca L. , Ayres James W. , Mackichan Janis J. , Wagner John G.
Published: October 2006

Dissolution profiles in 0‐1N hydrochloric acid using both the paddle stirrer apparatus and the spin filter apparatus were obtained for prednisone tablets made by seven different manufacturers and prednisolone tablets made by eight different manufacturers. Dissolution parameters were correlated with results obtained in three human bioavailability trials which were previously reported. Also, results obtained in one apparatus were correlated with those obtained in the other apparatus. Such correlations may be useful in the setting of in vitro dissolution rate specifications for commercial prednisone and prednisolone tablets.
Disposition of 5‐fluorouracil during chronic hepatic arterial infusion to patients with carcinoma in the liver and effect on circulating platelets
Authors: Sitar Daniel S. , Ruedy John R. , Shaw Douglas H. , Maksymiuk Andrew W. , Thirlwell Michael P.
Published: October 2006

5‐Fluorouracil was administered by continuous hepatic intra‐arterial infusion to eight patients with the diagnosis of cancer of the gastrointestinal tract and hepatic metastases. Its elimination characteristics were investigated to see if they correlated with therapeutic effect or reduced clinical toxicity when the drug was given by this route. Urinary excretion of drug and metabolites was similar to findings after intravenous bolus doses. Disposition changes could not be correlated with therapeutic effect or clinical toxicity. A dose‐related biphasic effect of 5‐fluorouracil was found on circulating platelets. Doses greater than 6 mg kg−1 d−1 decreased the number of circulating platelets, while doses less than that resulted in an increase in circulating platelets. Further studies are required to determine the mechanism of the effect of 5‐fluorouracil on platelets.
The renal clearance of disopyramide after bolus intravenous injection
Authors: Lawrence J. R. , Bryson S. M. , Sumner D. J. , Campbell B. C. , Whiting B.
Published: October 2006

Following bolus intravenous injection of disopyramide in eight normal volunteers the renal clearance of the drug appeared to fall with time. In the first two hours after injection renal clearance had a mean value of 89·0 ml min−1and fell to 29·4 ml min−1between 48 and 72 h.

In a separate study disopyramide was given by continuous intravenous (i.v.) infusion for 8 h following a loading dose of the drug. Renal clearance of disopyramide was thus estimated hourly over three narrow serum concentration ranges in a single volunteer. The estimate of renal clearance of the drug over the first hour following the start of these infusions was considerably in excess of values obtained later in the experiments.

The change in disopyramide renal clearance following bolus injection is partially time‐dependent. There are, however, fallacies in calculating short‐term clearance values after bolus drug injection from the venous concentration‐time curve and these may partially explain the change in renal clearance of disopyramide with time.
Measurement of plasma concentrations of isosorbide dinitrate
Authors: Doyle E. , Chasseaud L. F. , Taylor T.
Published: October 2006

Concentrations of the vasodilator isosorbide dinitrate (ISDN) in human plasma can be measured with good sensitivity (about 0·2–0·5 ng ml−1) using electron‐capture gas chromatography after a one‐stage extraction. The mean recovery of ISDN from plasma was 83 per cent ± 9 standard deviation (S.D.). The precision of the method for the measurement of ISDN in plasma ranged from ± 14 per cent at 1 ng ml−1 to ± 7 per cent at 5 ng ml−1 to ± 4 per cent at 50 ng ml−1. The 95 per cent confidence limits of the least‐squares regression calibration line forced through the origin were ± 100 per cent at 1 ng ml−1, ± 11 per cent at 10 ng ml−1, and ± 8 per cent at 30 ng ml−1. The method has been used to assay many samples withdrawn after doses of drug at therapeutic levels to normal subjects.
Dose‐dependent disposition of oral propranolol in normal subjects
Authors: Mackichan Janis J. , Pyszczynski Dennis R. , Jusko William J.
Published: October 2006

The pharmacokinetics and relative systemic availability or oral propranolol were studied in three healthy volunteers following administration of 10, 40, and 80 mg of propranolol hydrochloride. Plasma concentrations of propranolol were determined using a sensitive and specific fluorometric high pressure liquid chromatographic technique. In the dosage range studied, the amount of propranolol reaching the systemic circulation increased with dose, while half‐lives remained unchanged. The apparent ‘threshold dose’ for propranolol was much smaller than previously reported, and its contribution to the observed dose‐dependent availability is doubtful. Apparent intrinsic clearance values were shown to decrease with increase in dose, with a true maximal intrinsic clearance of 5·4 1kg−1 h−1. These data suggest the saturation of a low capacity enzyme system in the liver and are consistent with theoretical characteristics of a drug that is extensively metabolized during its first pass through the liver.
Disposition of intravenous theophylline‐7‐acetic acid in rabbits
Authors: Owen J. A. , Nakatsu K.
Published: October 2006

Theophylline‐7‐acetic acid (T7AA) was administered intravenously to rabbits so that its distribution and rate of elimination could be ascertained. The analytical techniques used were liquid scintillation counting (14C) and high pressure liquid chromatography. T7AA was eliminated rapidly in the urine; the T½ was 11·6 min. This drug appears to accumulate in the kidney because after 60 min, approximately 15 per cent of the intravenous dose was found in that organ.
Pharmacokinetic characteristics of two different formulations of trimipramine determined with a new GLC method
Authors: Caillé Gilles , Besner Jean‐Guy , Lacasse Y. , Vézina M.
Published: October 2006

A sensitive and specific gas chromatographic method using a nitrogen detector for the measurement of trimipramine plasma concentrations is described. This method was used to determine the relative bioavailability and some pharmacokinetic parameters of two formulations, tablets and capsules, in healthy volunteers. It was concluded the tablet and capsule formulations were pharmacokinetically equivalent.
Blood cyanide levels in mice after administration of amygdalin
Authors: Hill Helene Z. , Backer Ronald , Hill George J.
Published: October 2006

Oral doses of amygdalin and intraperitoneal (i.p.) doses of potassium cyanide (KCN) in the near‐lethal range were administered to CD2F1 female mice. Blood cyanide levels were then measured as a function of time. The maximum cyanide level after amygdalin administration was reached at about 1½ to 2 h and was within the range of values seen after KCN administration. Behaviour of mice correlated with the time of maximum blood cyanide level. Acute distress was observed at times when the cyanide level was highest. There was great variability in the nature and magnitude of the response in individual mice. The ability of the contents of various regions of the gastrointestinal tract and of tumour tissue to release cyanide from amygdalin was assessed. Stomach and upper intestine had little activity while the lower end and the faeces released large amounts. Again, there was a large variation between mice. These results are interpreted to mean that enteric contents are primarily responsible for the release of cyanide from ingested amygdalin. Freshly minced tumour tissue released negligible amounts of cyanide. Ten‐fold higher doses of amygdalin administered i.p. produced very small increases in blood cyanide levels and no toxic behaviour. The doses used are comparable to doses which might be ingested by patients receiving oral amygdalin or Laetrile and indicate that oral amygdalin is potentially extremely dangerous.
Bioavailability of atenolol formulations
Authors: McAinsh James , Simpson Wilfred T. , Holmes Brian F. , Young Jean , Ellis Stuart H.
Published: October 2006

In this comparative bioavailability study two tablet formulations of atenolol (sales and clinical trial) were compared with an oral solution. Twelve healthy adult male volunteers received, on a cross‐over basis, on three separate occasions, 100 mg oral dose of the three formulations of atenolol. Bioavailability was based on concentrations of atenolol in whole blood and urine. The atenolol blood levels peaked at approximately 3 h after dosing, with individual values ranging from 0·21 to 0·92 μg ml−1 (a four‐fold difference), with all three formulations. Three‐fold variations among subjects occurred in the areas under the curve (AUC) and urinary recoveries. The average elimination half‐life of atenolol was between 6 and 7 h for all three formulations. Some statistically significant differences were observed between the tablets and the aqueous solution: the AUC (∞) and mean peak blood concentrations were significantly greater with the U.K. sales tablet than the solution, and the mean concentrations in the blood at certain specified times after administration were significantly greater with the two tablet formulations than the solution. The profiles of absorption and excretion of the two tablet formulations were similar.

No adverse reactions were encountered in this study and all subjects completed the study without incident.
Review article cisplatin: Chemistry, distribution and biotransformation
Authors: Long D. F. , Repta A. J.
Published: October 2006

A review of the use of cisplatin in cancer chemotherapy in humans is presented. The emphasis is placed on the chemistry, in vivo distribution and biotransformation of this agent. The existing literature pertinent to the physicochemical properties of cisplatin and structure activity relationships of platinum coordination complexes is reviewed. The chemistry of this drug, both in aqueous media and in biological systems is discussed as well as current analytical methodology used for monitoring ‘cisplatin levels’ in biological fluids. Recent advances in analytical methodology specific for cisplatin are also presented and recent findings in the area of the possible biotransformations of this important anticancer agent are discussed.
Detection and metabolism of fencamfamine and the influence of acetazolamide on its urinary excretion
Authors: Delbeke F. T. , Debackere M.
Published: October 2006

A gas‐chromatographic (g.l.c.) method with electron‐capture (e.c.) detection is described for the simultaneous quantitative determination of nanogram concentrations of 2‐ethylamino‐3‐phenyl‐norbornane (Fencamfamine, REACTIVAN®) and its metabolite 2‐amino‐3‐phenylnorbornane in urine.

The renal excretion of fencamfamine and its metabolite after oral administration to humans was followed over a period of several days. The excretion of both substances was affected by urinary pH. Excretion peaks were obtained 2–4 h after ingestion and the total amount excreted during 80 h varied from 11.9 to 33.2 per cent. Based on urinary values, the biological half life of fencamfamine was 16 h.

The intake of acetazolamide shortly after fencamfamine resulted in a decrease of the fencamfamine excretion and a suppression of the metabolite output during at least 10 h. Acetazolamide did not influence the percentage of the doses excreted during 80 h.

No changes occurred in urinary fencamfamine or metabolite concentrations during storage of the urine at — 18° for 6 weeks.
The effect of increased caffeine intake on the metabolism and pharmacokinetics of theophylline in man
Authors: Monks T. J. , Lawrie C. A. , Caldwell J.
Published: October 2006

The metabolism and pharmacokinetics of intravenously administered theophylline (100 mg) have been investigated in three healthy male volunteers who consumed 6 bottles day of a cola beverage, in addition to their usual intake of methylxanthines, for 7 days prior to and during the study. Five urinary metabolites were detected in addition to unchanged theophylline, that is 3‐methylxanthine, 1.3‐dimethyluric acid, 1‐methyluric acid, and two minor unknown metabolites. The elimination of theophylline, 1.3‐dimethyluric acid, 1‐methyluric acid, and the two unknowns was described by first‐order kinetics, whereas that of 3‐methylxanthine was described by Michaelis‐Menten kinetics. The results have been compared with those previously obtained in the same volunteers while consuming their usual intake of methylxanthine‐containing foods and beverages, and this shows that the addition of extra methylxanthines to the diet does not influence the disposition of theophylline. This is in marked contrast to the effect of deprivation of dietary methylxanthines on theophylline metabolism. The results are discussed in terms of the influence of methylxanthines on theophylline metabolism, and of its possible dose‐ dependency.
Bioavailability of sustained release propranolol formulations
Authors: McAinsh James , Baber Nigel S. , Holmes Brian F. , Young Jean , Ellis Stuart H.
Published: October 2006

In this comparative bioavailability study two sustained release capsule formulations of propranolol, one a clinical trial formulation and the other the U.K. sales formulation (‘Inderal’ LA), were compared with a conventional ‘Inderal’ tablet. Twelve healthy adult male volunteers received, on a cross‐over basis, on three separate occasions, 160 mg oral doses of three formulations of ‘Inderal’. Bioavailability was based on concentration of propranolol in whole blood. The peak blood level and area under the propranolol blood level curve fell as the dissolution time increased. The half‐lives of the three formulations were inversely proportional to their dissolution rates, those of the sustained release formulations being considerably longer than that of the conventional tablet.

The 160 mg ‘Inderal’ tablet produced a rapid 90‐fold decline over 24 h in propranolol blood levels following a high initial peak. By comparison both sustained release formulations showed a less rapid fall in systemic levels and gave higher blood levels at the end of 24 h and plateau values between 8 and 14 ng ml −1.

The ‘Inderal’ LA sustained release formulation gave consistently higher propranolol blood levels than the clinical trial sustained release formulation. This result is in good agreement with their dissolution profiles. The lowering of the systemic bioavailability as the dissolution time increases is thought to be due to an increased metabolism of propranolol.
The concentrations of cephalosporins in tissue fluid of rats with localized infection
Authors: Polacek I.
Published: October 2006

Rats implanted with multiperforated subcutaneous plastic capsules were used as a model for study of the penetration of four cephalosporins into sites infected with Escherichia coli. The concentrations of the antibiotics were determined in uninfected and infected cages microbiologically up to 4 h after treatment. All four cephalosporins entered infected capsules faster than the control ones and the peak concentrations were attained 30–60 min earlier. The clearance of the antibiotics from infected capsules was faster than from uninfected ones, probably due to inactivation by microbial β‐lactamase(s). Serum protein binding may account for differences in the penetration rate of cephalosporins, but serum level and serum half‐time seem to contribute to their kinetic profile in tissue fluid.
The pharmacokinetics of acebvutolol in man, following the oral administration of acebutolol hcl as a single dose (400 mg), and during and after repeated oral dosing (400 mg, b.d.)
Authors: Gulaid A. A. , James I. M. , Kaye C. M. , Lewellen O. R. W. , Roberts E. , Sankey M. , Smith J. , Templeton R. , Thomas R. J.
Published: October 2006

The pharmacokinetics of acebutolol have been studied in eight healthy male volunteers following the oral administration of acebutolol hydrochloride (‘Sectral’, May & Baker) as a single dose (400 mg), and during and after repeated oral dosing (400 mg, b.d. for 56 days).

Following single dose administration, considerable inter‐subject variation in plasma levels of parent drug and the major metabolite, diacetolol. was evident. Acebutolol appeared to be eliminated from plasma in a bi‐phasic manner, and this was confirmed from urinary excretion rate data. Mean initial and terminal half‐lives of about 2 and 11 h, respectively, were determined. Plasma levels of diacetolol were greater than those of parent drug from 3 to 4 h following dose administration. Total urinary excretion of diacetolol was generally greater than that of acebutolol.

During repeated dosing, steady‐state plasma levels of acebutolol and diacetolol were achieved in 6 volunteers. Acebutolol did not appear to stimulate or inhibit its metabolism.
Butriptyline: Human pharmacokinetics and comparative bioavailability of conventional and sustained release formulations
Authors: Bourgouin Jean , Gagnon Marc‐Andre , Elie Robert , Dvornik Dushan , Gonzalez Ramona , Kraml Michael
Published: October 2006

The pharmacokinetics and relative bioavailability of butriptyline from conventional and a sustained release (SR) formulation have been studied in a panel of 14 volunteers. A single oral dose of 75 mg butriptyline hydrochloride was administered and a 2 × 2 latin square design was followed. Pharmacokinetic modelling has shown that the plasma butriptyline concentration/time profile is adequately described by a two‐compartment open model; good agreement was obtained for the model‐fitted and measured parameters. The SR formulation was shown to possess sustained release characteristics as evidenced by the increase in Tmax for 2.6 to 7.5 h, the decrease in Cmax from 46.5 to 20.3 ng ml−1, and a three‐fold increase in ‘half‐value duration’ (HVD). The changes have been achieved without any significant decrease in the relative bioavailability of the SR formulation. The half‐life of butriptyline in plasma was about 20 h and was not formulation dependant.
Rifaprim (rifampicin plus trimethoprim): Pharmacokinetics and effects on the normal flora of man
Authors: Brumfitt W. , Hamilton‐Miller J. M. T.
Published: October 2006

Ten healthy volunteers were given ‘Rifaprim’ in the dosage recommended for the treatment of urinary infections in man (rifampicin 300 mg + trimethoprim80 mg in the morning and double these amounts at night, for 7 days). Levels of both drugs in the serum and urine were determined on the first and last days. The results show that trimethoprim was always present in the serum in amounts sufficient to suppress the emergence of resistance to rifampicin. In the urine, inhibitory concentrations of each drug were present throughout the course of treatment. Aerobic organisms were largely eliminated from the gut and reappeared after treatment still sensitive to both antibiotics: the anaerobic moiety persisted and became resistant to rifampicin. Changes in nasopharyngeal flora were relatively minor. Thus, this dosage regimen of ‘Rifaprim’ contains enough trimethoprim to prevent the emergence of resistance to rifampicin among urinary pathogens under normal circumstances (i.e. provided the organisms are initially sensitive to trimethoprim).
The assay and absorption kinetics of oral theophylline−7‐acetic acid in the human
Authors: Sved S. , McGilveray I. J. , Beaudoin N.
Published: October 2006

A sensitive and specific method for the estimation of theophylline−7‐acetic acid in plasma by high performance liquid chromatography is described. Acidified plasma is extracted with chloroform‐n‐butanol (85: 15), back extracted with phosphate buffer (0.5 moll−1, pH 6.5), and finally the acidified aqueous phase extracted again with chloroform‐butanol. After evaporation of the extract the residue is redissolved in the chromatographic mobile phase (hexane‐dichloromethane‐ethanol‐acetic acid, 10:86: 3:1) and chromatographed on silica gel. The method was used to follow the plasma theophylline‐7‐acetic acid concentrations in two volunteers after single oral doses of 1.0 g of the drug. The results confirm previous reports, based on urine data and on plasma data following intravenous administration, that the drug is poorly absorbed (apparent bioavailability of 1 and 2 per cent), rapidly eliminated (half‐life of 1.0 and 2.4 h) and not converted to theophylline.
Age‐related differences in ophthalmic drug disposition I. Effect of size on the intraocular tissue distribution of pilocarpine in albino rabbits
Authors: Miller Susan C. , Patton Thomas F.
Published: October 2006

It has previously been documented that substantially different aqueous humour drug levels are observed in rabbits of different ages when the same dose of pilocarpine is instilled into the eye. Also, it has been shown that the aqueous humour volume ratio for rabbits of different ages can be used to predict aqueous humour levels of pilocarpine attained after topical dosing. In the present study, concentrations of pilocarpine in the cornea, aqueous humour, iris‐ciliary body, lens, and vitreous humour were determined in both 20‐day old and 60‐day old rabbits following the topical administration of identical doses of drug. For tissues other than the aqueous humour and iris‐ciliary body, consideration of only tissue size differences between rabbits of different ages will not suffice to explain the observed differences in pilocarpine concentration. Any attempt to develop rational age‐related dosage modifications for ophthalmic drugs must include a consideration of functional and developmental differences as well as size effects.
Pharmacokinetic evaluation of betameth asone and its water soluble phosphate ester in humans
Authors: Loo J. C. K. , McGilveray I. J. , Jordan N. , Brien R.
Published: October 2006

Two betamethasone tablet formulations, and a betamethasone phosphate solution were compared in a plasma level study. The tablet formulations (A and B) and a solution of betamethasone phosphate (C) were administered in single 2 mg doses to nine volunteers according to a three times repeated Latin square design. Plasma samples were obtained over 27 h following each dose and plasma was analysed for betamethasone by radioimmunoassay.

Pharmacokinetic evaluation of the data, obtained according to the one‐compartment open model, indicated that there were no significant differences between the extent of absorption, and the first‐order elimination rate constants. As would be expected, the solution (C) gave a faster absorption rate than tablets A and B.
Comparative binding affinities of tamoxifen, 4‐hydroxytamoxifen, and desmethyltamoxifen for estrogen receptors isolated from human breast carcinoma: Correlation with blood levels in patients with metastatic breast cancer
Authors: Fabian Carol , Tilzer Lowell , Sternson Larry
Published: October 2006

The relative ability of the antiestrogen, tamoxifen, and its monohydroxy and desmethyl metabolites to displace tritiated estradiol from estrogen receptors isolated from human breast carcinoma was determined. 4‐Hydroxytamoxifen binds to the estrogen receptor with affinity equal to estradiol, and with 25–50 times higher affinity than does tamoxifen. Desmethyltamoxifen binds to the estrogen receptor with < 1 per cent of the affinity of tamoxifen. Blood level determinations of tamoxifen species in breast cancer patients receiving the drug indicated that after 3 weeks of therapy, desmethyltamoxifen levels were 1.2–1.8 times greater than tamoxifen levels and 4‐hydroxytamoxifen levels were 2–18 per cent of parent drug concentrations. Thus, because of its high affinity for the estrogen receptor, the 4‐hydroxy metabolite may play a significant antiestrogenic role following tamoxifen therapy, despite its low relative abundance. Desmethyltamoxifen, on the other hand, may have only minor importance as an anti‐estrogenic agent following tamoxifen treatment, due to its poor affinity for the estrogen receptor coupled with blood levels that are at most 75 per cent greater than tamoxifen levels at steady state.
HPLC determination of benzthiazide in biologic material
Authors: Meyer Marvin C. , Hwang Philip , Straughn Arthur B. , Rotenberg And Keith
Published: October 2006

An assay was developed for benzthiazide in plasma, urine and feces, using high performance liquid chromatography (HPLC). A reverse‐phase column was employed, with quantitation at 280 nm, using polythiazide as an internal standard. In three of four human subjects who received a 50 mg benzthiazide tablet the plasma concentrations were below the 10 ng ml−1 sensitivity limit of the assay, and the urinary recovery averaged less than one per cent of the dose. One subject received a 50 mg dose as both a tablet and a solution; the urinary recoveries for these two doses were 1.7 and 10.4 per cent, respectively. Fecal samples, obtained from two subjects who received 50 mg tablets, were estimated to contain approximately 80 per cent of the administered dose.
Quantitation of iprindole in plasma by GLC
Authors: Caillé G. , De Montigny C. , Besner J‐G.
Published: October 2006

A specific, sensitive, rapid, and reproducible method for iprindole in human plasma was developed using gas chromatography with trimipramine as internal standard. The sensitivity of the method is of S ng ml−1 and a linearity was obtained for concentrations ranging from 12.5ngml−1 to 100ngml−1 with a regression coefficient of 0.9872. The plasma levels of iprindole were determined in five healthy volunteers following the administration of a single oral dose of 60 mg and in four patients admitted for endogenous depression after a 3‐week administration of 90mgd−1. Following a single oral dose to healthy volunteers, the maximum concentrations occurred between 2 and 4h after administration of the drug and the mean half‐life value was 52.5 h. In patients the steady‐state concentrations of iprindole ranged between 18 and 77ngml−1.
Antipyrine clearance, aminopyrine N‐demethylase, and bilirubin udp‐glucuronyl transferase activity in patients with amoebic liver abscess
Authors: Narang A. P. S. , Datta D. V. , Mathur V. S.
Published: October 2006

Three indices of drug metabolism, antipyrine clearance in vivo, and aminopyrine N‐demethylase and bilirubin UDP‐glucuronyl transferase activity in liver biopsies, were studied in fifteen patients with amoebic liver abscess (with and without jaundice). The mean (± S.E.) antipyrine half‐life in patients with jaundice was 21.64 (±1.52)h and in patients without jaundice was 19.36 ( ± 0.93)h. It was significantly prolonged in both groups of patients as compared to controls (11.63 ± 0.86 h). It showed a good correlation with serum albumin (p<0.01), prothrombin time index (p<0.01), and aminopyrine N‐demethylase (p<0.05). Aminopyrine N‐demethylase was found to be decreased in patients without jaundice but no significant change could be observed in patients with jaundice. Bilrubin UDP‐glucuronyl transferase showed no significant change in either of the groups.
The effect of hydralazine on the pharmacokinetics of three different beta adrenoceptor antagonists: Metoprolol, nadolol, and acebutolol
Authors: Jack David B. , Kendall Martin J. , Dean Sandra , Laugher Steven J. , Zaman Razia , Tenneson Michael E.
Published: October 2006

The effect of hydralazine on the pharmacokinetics of metoprolol, nadolol, and acebutolol has been studied by measuring drug concentrations in plasma, serum, and urine. Metoprolol is affected by hydralazine, the AUC and Cmax being significantly increased. The kinetics of acebutolol and its major metabolite, diacetolol, are unaffected. Poor absorption of the polar beta blocker, nadolol, does not allow a firm conclusion to be drawn regarding the effect of hydralazine. It is concluded that only beta blockers with a substantial first‐pass loss are likely to be significantly affected by hydralazine.
Bioavailability of phenylbutazone from a new enteric‐coated formulation with superior dissolution characteristics
Authors: John V. A. , Goldsborough S. , Morrison P. J. , Rogers H. J. , Spector R. G. , Bradbrook I. D.
Published: October 2006

The bioavailability of an improved formulation of enteric‐coated phenylbutazone with faster dissolution, more consistent in vitro rate of drug release and improved stability was compared in 8 normal subjects at doses of 100 and 200 mg with commercially available Butacote®. Phenylbutazone was more rapidly absorbed from the new formulation and higher plasma concentrations were achieved at shorter intervals after dosing.

Drug elimination rate was unaffected by reformulation and despite faster absorption the total amounts of drug reaching the circulation from the new and commercial products were similar. It was concluded that replacing Butacote® by the new formulation would provide the same therapeutic benefit.
Relative bioavailability of acetazolamide tablets
Authors: Straughn Arthur B. , Gollamudi Ramachander , Meyer Marvin C.
Published: October 2006

Plasma acetazolamide concentrations were determined enzymatically after administration of three tablet dosage forms and a reference solution to 12 human subjects in a crossover study. Two of the tablet products represented different lots from the same manufacturer. There were no significant differences in area under the plasma level‐time curves among the four treatments. However, significant differences were found among tablets in terms of peak plasma concentration and time to reach peak concentration. These apparent differences in rate of absorption were correlated with in vitro dissolution data obtained in pH 1.5 dissolution medium.
Bioavailability of chlorothiazide from 50, 100, and 250 mg solution doses
Authors: Osman M. A. , Patel R. B. , Irwin D. S. , Craig W. A. , Welling P. G.
Published: October 2006

The bioavailability of chlorothiazide was examined following single oral solution doses to eight healthy male volunteers. Drug was administered in 250ml of water after overnight fast. Bioavailability was determined by measuring 72 h urinary recovery of unchanged drug. Mean urinary recovery from 50, 100, and 250 mg doses was, respectively, 28.3, 47.0, and 83.3 mg, representing 56.4, 47.0, and 33.3 per cent of the administered dose. The correlation coefficient between dose size and percentage recovery was −0.662. These results add support to previous suggestions that the absorption of chlorothiazide from the gastrointestinal tract is saturable, and that the bioavailability of chlorothiazide may be similar to that of hydrochlorothiazide when these compounds are administered in the same dosage range.
Salicylamide pharmacokinetics in healthy males: Dietary effect
Authors: Morad Abdel‐Rehim M.
Published: October 2006

The effect of diet on the absorption, metabolism, and elimination of salicylamide (SAM) in man was studied in five healthy male volunteers. In a three‐way cross‐over study, 300 mg SAM capsules were administered under fasting, carbohydrate, and lipid diet conditions. Total urinary salicylates, salicylamide glucuronide (SAMG), and salicylamide sulphate (SAMS) were determined at different time intervals. Diet was found to have no significant effect on the extent of SAM absorption or on its apparent elimination half‐life. A significant increase (P< 0.001) in the fraction excreted as SAMS in the lipid diet trial compared to the fasting or carbohydrate trials is observed. In the lipid diet trial, the ratio (R) of the cumulative urinary SAMS/SAMG was found to be 1.5–3 times the ratio obtained under fasting or carbohydrate diet conditions. The equilibrium solubilities of SAM under physiologic conditions in water (W), simulated intestinal fluid (M), and corn oil (O) were 4.08, and 4.81, and 12.5mgml−1, respectively. The equilibrium apparent distribution coefficients KO/W'KO/W, and KM/W were 3.1, 2.6, and 1.18, respectively. The increase in R is probably due to a decrease in free SAM concentration at the absorption site (intestinal mucosa) in the presence of lipids. A model for drug distribution in the gastrointestinal tract during lipid digestion is proposed and discussed.
Buccal uptake, urinary excretion, and physicochemical properties of zipeprol and its N‐dealkylated products
Authors: Achari R. , Beckett A. H.
Published: October 2006

Buccal uptake, partition characteristics, ionization constants, and urinary excretion were studied for zipeprol and two of its metabolities. Buccal uptake, measured in a single subject, was found to be correlated with n‐heptane/water (ph 7.4) partition values of the compounds, and with proportional excreation of the unchanged drug. The importance of the shape of buccal uptake‐pH curves in the prediction of absorption and excretion of these compounds is discussed.
Excretion of digoxin and its metabolites in urine after a single oral dose in healthy subjects
Authors: Magnusson J. O. , Bergdahl B. , Bogentoft C. , Jonsson U. E. , Tekenbergs L.
Published: October 2006

The 3‐day urinary excretion of digoxin, its conjugated and unconjugated hydrolytic metabolites and dihydrodigoxin, was studied in 8 healthy men after oral administration of tritiated digoxin. Analysis was performed by high pressure liquid chromatography (HPLC). The total radioactivity corresponded to 45.4±2.0 per cent (mean ± S.E.M.) of the dose. By HPLC 424 ± 2.7 per cent was recovered before and 44.0 ± 2.7 per cent after deconjugation of the samples. Digoxin and dihydrodigoxin constituted 40.3 ± 2.9 per cent; of this 0.7 ± 0.4 per cent was dihydrodigoxin. The sum of the hydrolytic metabolites was 2.1 ± 0.3 per cent before and 3.4± 0.5 per cent after deconjugation. No correlation was found between gastric pH and the production of hydrolytic metabolites. The relative amount of these metabolites was maximal (mean 13.4 per cent of the excretion) in the 4.8 h sampling period. During the first 8 h an average of 8.6 per cent of the radioactivity was not recovered by HPLC. The metabolism of digoxin as judged by urinary excretion was limited and showed great variation during the early hours after treatment. The excretion of unchanged digoxin in some individuals constituted as little as 60 per cent over the first 12 h after dosing.
Effect of sustained release on the pharmacokinetic profile of indomethacin in man
Authors: Yeh K. C. , Berger E. T. , Breault G. O. , Lei B. W. , McMahon F. G.
Published: October 2006

The effect of sustained release on the pharmacokinetic profile of indomethacin was examined by comparing to three reference regimens: an intravenous dose, a single 75 mg dose of conventional capsules, and three 25 mg conventional doses given at 4‐h intervals. Results indicate that the sustained release test formulation exhibited more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion, and showed an overall bioavailability of 0.93 (95 per cent C.I. = 0.82, 1.04) relative to three 25 mg doses of the conventional capsules.
The disposition of diphenhydramine and four of its analogues in rabbits and implication for structure‐activity relationship studies in drug design
Authors: Parry Rosalind , Calvert R. T.
Published: October 2006

The disposition of diphenhydramine (I) and four of its ring substituted analogues, 4‐bromodiphenhydramine (II), 4‐methyldiphenhydramine (III), 2‐methyldiphen‐hydramine (IV), and 4‐t‐butyldiphenhydramine (V), was investigated in the rabbit, during and after intravenous infusion.

The concentration of each analogue was determined by gas‐liquid chromatography (GLC) and the disposition parameters of clearance, volume of distribution, and elimination rate constant determined. These parameters were found to vary within the series, clearance increased in the order I < IV < III < II < V and volume of distribution in the order III < I < IV < V < II. These changes correlated with the Hansch hydrophobic substituent parameter: for clearance r = 0.97, for volume r = 0.7.

The implication of these changes for the design of studies investigating the effects of structure on pharmacological response are discussed.
Pharmacokinetics of 14C‐DMPS (sodium‐1,3 14C‐2,3‐dimercaptopropane‐l‐sulphonate) in beagle dogs
Authors: Wiedemann P. , Fichtl B. , Szinicz L.
Published: October 2006

The pharmacokinetics of labelled DMPS (sodium‐1,3 14C‐2,3‐dimercaptopropane‐1‐sulphonate) have been studied in four beagle dogs following bolus intravenous injection (65‐7 μmolkg−1) and oral administration (197μmol kg−1). Following intravenous injection the main kinetic parameters were t1/2 = 43min, Vβ = 160 ml kg−1, and plasma clearance Clp = 2.6ml min−1 kg−1.

Following oral administration 14C‐DMPS is rapidly absorbed with peak concentrations (478 ± 25 umol 1−1) measured after 30–45 min. About 60 per cent of the oral dose was absorbed. Estimates of t1/2, Vβ, and Clp after oral administration were in close agreement with the values obtained in the intravenous study.

14C‐DMPS is eliminated from the body by the kidneys. About 70 per cent of 14C‐DMPS in dog plasma are bound to proteins. Binding is even higher in plasma from rat and man.
Comparative bioavailability of S‐carboxymethylcysteine from two dosage forms: Hard gelatin capsule and syrup
Authors: Aiache J‐M. , Borel J. P. , Kantelip J‐P.
Published: October 2006

Measurement of plasma concentrations after the oral administration of S‐carboxymethylcysteine in two different dosage forms, as a hard gelatin capsule and as a syrup, shows its relative bioavailability from the two formulations to be similar. With the exception of the time required to reach peak concentration, which shows a slight variation attributable to the time taken for the drug to be released from the capsule and to dissolve, parameters such as peak concentration, biological half‐life and area under the serum‐concentration curve whether from t=0 to t = 8h or from t = 0 to t=∞, are not statistically different. The areas under the plasma‐concentration curves between t = 0 and t = 8 h and between t = 0 and t = ∞ shows that for a confidence limit of 95 per cent, the mean for the capsular form does not differ by more than 3.3–10.3 per cent from the mean for the syrup.
Esterase distribution in the rabbit cornea and its implications in ocular drug bioavailability
Authors: Lee Vincent H.‐L. , Morimoto Kim W. , Stratford Robert E.
Published: October 2006

Being the major pathway by which topically applied ophthalmic drugs enter the eye, the cornea can control the amount of active drug ultimately absorbed by offering resistance to drug permeation and by metabolizing the drug during permeation. This research seeks to determine the esterase activity in the cornea and two of its component layers— epithelium and stroma‐endothelium—so as to anticipate the extent to which drugs containing ester linkages will be metabolized during transport. This has been achieved by incubating corneal homogenates of albino and pigmented rabbits of various age groups with α‐naphthyl acetate, the model substrate, and monitoring the fluorescence intensity due to α‐naphthol as a function of time. The results indicate that: (1) esterase activity in the epithelium is approximately twice that in the stroma‐endothelium; (2) esterase activity in the intact cornea is linearly related to those in the epithelium and the stroma‐endothelium; and (3) the esterase activity in the cornea and its component layers varies with rabbit's age and strain. According to these results the bulk of esterase‐mediated hydrolysis is expected to take place in the epithelium, so that the residence time of a drug in this tissue can have a significant impact on its ocular bioavailability.
Bioavailability of a commercial sustained‐release quinidine tablet compared to oral quinidine solution
Authors: Sawyer William T. , Pulliam Charles C. , Mattocks Albert , Foster James , Hadzija B. Wesley , Rosenthal Harold M.
Published: October 2006

The bioavailability of quinidine sulfate after oral administration of a commercial sustained‐release quinidine tablet was compared with that of oral quinidine sulfate solution in 18 normal subjects. Three hundred milligrammes of each product was administered to each subject in standard cross‐over fashion on separate occasions, with plasma quinidine levels measured for 46 h after each dose. Although peak plasma quinidine levels were lower, and occurred later, after tablet administration than after solution, analysis of the area under the plasma quinidine level‐time curve (AUC) values for each product indicated that the products were equivalent, in terms of the extent of absorption, with the mean AUC (0–46h) value for the tablet, 8744.4 ng × h ml−1, comparable to that of the solution, 9145.9 ng × h ml−1.
Bioavailability of bromhexine tablets and preliminary pharmacokinetics in humans
Authors: Bechgaard E. , Nielsen Anni
Published: October 2006

The absorption of bromhexine from Bromhexin tablets 8 mg, DAK has been compared with that from Bisolvon® tablets 8 mg, Boehringer Ingelheim, in a two‐way complete crossover study. Four tablets of each of the two bromhexine products, corresponding to a single dose of 32 mg of bromhexine hydrochloride (77.6 μmol), was administered to each of the 10 volunteers. The plasma concentration was followed over the 4‐hour period following each administration. By means of Pratt's test for paired data no statistically significant difference (p > 0.10) between the two products was found with respect to maximum plasma concentration (89 and 84nmol.l−1, respectively), the times for their occurrence (1.3 and 1.0h, respectively), and the area under the plasma concentration‐time curves (140 and 132 nmol.l−1.h, respectively). It is concluded that Bromhexin, DAK and Bisolvon® are bioequivalent.

Provisional pharmacokinetic data for bromhexine, after oral administration, in man were obtained. The first‐pass effect and the biological half‐life were estimated by combining plasma and 30 h urine data from four of the volunteers. The first‐pass effect was estimated to be c. 75 per cent, the biological half‐life to be c. 6 h, and c. 0.1 per cent of the dose was found as unmetabolized bromhexine in the urine. The data indicate that the pharmacokinetics of bromhexine may be described as a two‐compartment open model.
Dose‐dependent pharmacokinetics of furosemide in the rat
Authors: Hammarlund M. M. , Paalzow L. K.
Published: October 2006

The pharmacokinetics of furosemide were investigated in the rat at doses of 10 and 40mg kg−1 corresponding to doses of 80 and 320 mg given to humans based on body surface area. A three‐compartment open model with renal excretion taking place from the shallow peripheral compartment gave the best fit to the data. The terminal half‐life of furosemide was found to change from 29min for the 10 mg kg−1 dose to 49min for the 40 mg kg−1 dose. This change could be detected as a change in the apparent volume of distribution caused by decreased protein binding at increasing plasma concentrations of furosemide. The total plasma clearance did not change significantly although metabolic and renal clearances both changed. The renal clearance was found to be dependent on the free fraction of furosemide in plasma and thus increased with increasing plasma concentrations. The metabolic clearance decreased with increasing dose indicating a saturable metabolism of furosemide.
Kinetics of cocaine in humans after intravenous and intranasal administration
Authors: Javaid J. I. , Musa Mahmoud N. , Fischman Marian , Schuster C. R. , Davis John M.
Published: October 2006

Cocaine kinetics were studied in four subjects after intravenous and intranasal administration. For intravenous administration cocaine hydrochloride (32 mg) dissolved in physiological saline was injected in 1 ml volume over a 1 min period. Intranasal cocaine was administered as 100mg powder consisting of an appropriate dose of cocaine hydrochloride (64 and 96 mg) mixed with lactose powder. Subjects were instructed to inhale the mixture through a 5 cm straw within 1 min. Cocaine kinetics, after intravenous injection, conform to a one‐compartment open model with first‐order elimination. After intranasal administration, cocaine kinetics conform to a one‐compartment model with first‐order absorpton and first‐order elimination. The mean half‐life of cocaine for intravenous injection in four subjects was 41·4±8·2 min (mean ± S.E.M.) and the range was 19 to 64min. There were statistically significant differences in the mean area under the concentration‐time curve (AUC) following intravenous and intranasal administration. The AUC was dose‐dependent and the fraction of the dose absorbed after 64mg intranasal cocaine was significantly lower than after 96 mg dose (p < 0·05).
Absorption of theophylline from enteric coated and sustained release formulations in fasted and non‐fasted subjects
Authors: Osman Mohamed A. , Patel Rajni B. , Irwin David S. , Welling Peter G.
Published: October 2006

The influence of prior food ingestion, and also of varying fluid volumes, on plasma theophylline levels was examined following single oral doses of two sustained‐release formulations, Theobid® (260 mg) and Theo‐Dur® (200 mg) and one partially enteric‐coated formulation, Choledyl® (128mg), to 9 healthy volunteers.

Prior food ingestion tended to delay the absorption of theophylline from all formulations to a small extent. This effect was observed only at early sampling times, and plasma drug profiles were similar for all treatments within a particular formulation.

Theobid® and Theo‐Dur® gave rise to plasma profiles that were characteristic of sustained‐release formulations, with mean Cmax values of 5·5−5·7 μgml−1 (Theobid®) and 2·8−3·2 μgmr−1 (Theo‐Dur®) occurring at 5·8−9·1 h after dosing. Choledyl® gave rise to a longer absorption lag time than the other formulations but was subsequently absorbed at a faster rate yielding mean Cmax values of 3·2−3·5μgml−1 at 2·8−4·1 h.

The intersubject variability in theophylline plasma levels, and also in most pharmaco‐kinetic parameter values, was generally less following Theo‐Dur® compared to the other formulations.