bluuebunny/crossref_metadata_2025 huggingface dataset:
Relative bioavailability of olsalazine from tablets and capsules: A drug targeted for local effect in the colon
Authors: Ryde M. , Huitfeldt B. , Pettersson R.
Published: October 2006

The aim of this investigation was to compare two formulations of the prodrug oisaiazine (OLZ) with regard to local bioavailability of 5‐aminosalicylic acid (5‐ASA) in the colon. Since 5‐ASA can not be measured directly in the colon, the bioavailability was evaluated by studying the plasma concentration and cumulative urinary excretion (Ae) of its main metabolite N‐acetyl‐5‐aminosalicylic acid (ac‐5‐ASA). The absorption of OLZ was also studied. A single dose of lg OLZ tablets and capsules was given to nine healthy fasting volunteers in two repeated two‐period cross‐over studies. Blood and urine samples were collected for 72 and 96h, respectively. AUC, Cmax and Ae data from both studies were combined for statistical analysis. Ninety per cent confidence limits for differences in mean AUC for ac‐5‐ASA (tablet‐capsule) compared to that of capsules were ‐0·31 per cent and 30·8 per cent. This indicates bioequivalence if a more relaxed criterion than the conventional ·20 per cent is applied, which is justified in this situation. The 90 per cent confidence limits for Cmax were ‐10·5 per cent and 36·9 per cent while for Ae the values were ‐20·5 per cent and 23·7 per cent. Within and between subject variability estimates for AUC of ac‐5‐ASA were 24 per cent and 46 per cent, respectively.
Metabolism of 14C‐2′,3′‐dideoxyinosine by the in situ perfused rat liver preparation
Authors: Tay Lee K. , Papp Eugene A. , Timoszyk Julita
Published: October 2006

The metabolism and biliary excretion of 14C‐dideoxyinosine (14C‐ddI) has been investigated using the in situ perfused rat liver (PRL) preparation. After 2h of perfusion through the liver, approximately 70–75 per cent of the total 14C‐radiolabel was recovered in the perfusion medium, less than 1 per cent was excreted in bile and 15–18 percent was retained in the liver. Hepatic clearance of ddI was 1·5 ± 0·1 ml min−1 and half‐life for the elimination of ddI from the medium was 22·9 ± 2·0 min (n = 3). Hepatic extraction was estimated to be 7·5 per cent. HPLC analysis of the effluent perfusate indicated that ddI was metabolized to hypoxanthine, xanthine, uric acid, and to a polar metabolite which was tentatively identified as allantoin. Approximately 60–65 per cent of the ddI dose was converted to allantoin after 2h of perfusion. Of the other three metabolites, uric acid levels increased to 20–30 per cent of the dose after 45 min and declined to about 5 per cent of the dose by the end of the perfusion period. Levels of hypoxanthine and xanthine were low and both compounds were not detected in the perfusate after 45 min post‐infusion. In bile, the major peak, which accounted for about 50 per cent of the 14C‐radiolabel co‐eluted with the putative metabolite, allantoin (0·4 per cent of the dose). Uric acid (0·06 per cent of the dose) was the only other metabolite detected in bile. These results suggest that biliary excretion is a minor pathway for the elimination of ddI. Furthermore, ddI is rapidly cleared and metabolized by the liver to hypoxanthine, xanthine, uric acid, and to allantoin.
Effects of phenobarbital and 3‐methylcholanthrene pretreatment on the pharmacokinetics and the pharmacodynamics of bumetanide in rats
Authors: Choi Young M. , Lee Sun H. , Jang Seong H. , Lee Myung G.
Published: October 2006

The effects of pretreatment with the enzyme inducers, phenobarbital (PB) and 3‐methyl‐cholanthrene (3‐MC), on the pharmacokinetic and pharmacodynamic parameters of bumetanide were examined in rats. The nonrenal clearance (19·3 vs 29·6 ml min−1 per kg) of bumetanide increased significantly in PB treated rats. This suggested that the nonrenal metabolism of bumetanide is increased by pretreatment with PB, which was supported by significantly increased amounts of bumetanide glucuronide and desbutyl bumetanide excreted in 8‐h urine, and reduced amounts of bumetanide remaining per gram of tissue after 30‐min incubation of 100 μg of bumetanide with the 9000 xg supernatant fraction of liver, stomach, and kidney tissue homogenates in PB treated rats. The contents of hepatic cytochrome P‐450 (1·29 vs 2·15 nmol mg−1 protein) and the weights of liver and stomach increased significantly in PB treated rats, suggesting that the metabolizing enzymes for bumetanide are induced by pretreatment with PB. The 8‐h urine output per 100g body weight was not significantly different by pretreatment with PB although the amounts of bumetanide excreted in 8‐h urine increased significantly in PB treated rats. It could be explained by the fact that the dose of bumetanide used results in urinary concentrations at the plateau of the concentration–effect relationship. Therefore, the alteration in the urinary excretion rate of bumetanide by pretreatment with PB would not alter the diuretic effect. In 3‐MC treated rats, pharmacokinetic and pharmacodynamic parameters were not significantly different and it suggested that the metabolizing enzymes for bumetanide are not induced by pretreatment with 3‐MC although the contents of hepatic cytochrome P‐450 and the weights of liver and stomach increased significantly by pretreatment with 3‐MC.
Comparison of in vitro and in vivo release characteristics of acetaminophen from gradient matrix systems
Authors: Van Bommel Elvira M. G. , Raghoebar Maikel , Tukker Josef J.
Published: October 2006

An effort was made to correlate the in vivo and in vitro release data of acetaminophen from two formulations of a recently developed controlled‐release system, the Gradient Matrix System (GMS‐1 and GMS‐2). The in vivo release curves, obtained by deconvolution of the plasma concentration time plots, showed a small inter‐subject variability. GMS‐1 with fastest in vitro release also showed fastest in vivo release. A good relationship was only found after time‐scaling of the release data.
Pharmacokinetic comparison of a combination tablet of enalapril and hydrochlorothiazide with enalapril and hydrochlorothiazide tablets administered together and separately
Authors: Howes L. G. , Conway E. L. , Phillips P. A. , Broadbear J. , Drummer O. H. , Louis W. J.
Published: October 2006

Enalapril and hydrochlorothiazide (HCT) are established single agent treatments for mild hypertension and cardiac failure and are a potent combination in more severe or resistant cases. We have compared the pharmacokinetics of enalaprilat (the active metabolite of enalapril) and HCT in a four‐way comparison of a combination tablet of enalapril (10mg)/HCT (25 mg) with a single dose of an enalapril tablet (10 mg), a single dose of a HCT tablet (25 mg) and simultaneous administration of separate tablets of enalapril (10 mg) and HCT (25 mg) in normotensive volunteers (n = 12, 21–26 years). Each subject received all four treatments and the study was conducted as a randomized, latin square, open design with at least 1 week washout between studies. Overall, HCT was bioequivalent under all conditions and enalaprilat was bioequivalent when given in combination with HCT either as one tablet or as two separate tablets. However, when given with HCT, the mean AUC and Cmax of enalaprilat were reduced up to 20 per cent compared with enalapril administered alone. This is unlikely to be of clinical significance as the differences did not reach statistical significance and the total enalaprilat excreted in the urine over 96 h was similar after all treatments.
Pharmacokinetics of azithromycin after single oral dosing of experimental animals
Authors: Davila D. , Kolačny‐babić Lidija , Plavšić F.
Published: October 2006

Azithromycin, a macrolide antibiotic with an enhanced antimicrobial spectrum, was found to have a longer half‐life than erythromycin, with marked tissue penetration. The pharmacokinetics of azithromycin after oral administration were compared with those of erythromycin in rats (200 mg kg−1) and rabbits (80 mg kg−1). Concentrations of azithromycin in liver, lung, kidney, ileum, and brain were higher than serum concentrations. The slow decline in tissue concentrations was evident from the biphasic elimination profile. Thus, advantageous pharmacokinetic properties and the broader antimicrobial spectrum of azithromycin relative to erythromycin appear to further support its therapeutic potential.
Dermal absorption of niclosamide in rats and minipigs
Authors: Brennan Patricia , Johnson Debra , Rider Susan , Cone Norm , Goldman Marvin , Buckpitt Alan , Chung Ho
Published: October 2006

The dermal absorption of niclosamide, a drug shown to prevent Schistosomiasis by blocking the dermal penetration of cercariae, has been examined in Sinclair minipigs and rats. Radioactivity in the urine and feces collected daily for 7 days after application of 14C‐niclosamide accounted for less than 2 per cent and 10 per cent of the labelled compound applied to pig and rat skin, respectively. Approximately 20 per cent of the radioactivity from the dose solution was recovered on the skin excised from the area of application in both minipigs and rats. No radioactivity was detected in organs removed from the pig 7 days after application of radiolabelled drug while less than 6 per cent of the dose could be accounted for in the rat organs/carcass. Radioactivity in swine blood, removed 0·5, 1, 2, 4 and at 24 h intervals after dosing, was at or below three times background in all of the samples. Total recovery of the applied radioactivity was 78 per cent in pigs and 57 per cent in rats. These studies indicate that niclosamide is very poorly absorbed after dermal application. The results are consistent with earlier comparative studies showing that dermal penetration of xenobiotics in rats is generally higher than in swine.
Factors influencing the protein binding of vancomycin
Authors: Shin Wan G. , Lee Myung G. , Lee Min H. , Kim Nak D.
Published: October 2006

Various factors influencing the protein binding of vancomycin were examined using equilibrium dialysis method. Four per cent human serum albumin (HSA) and/or 0·08 per cent alpha‐1‐acid glycoprotein (AAG), dissolved in isotonic phosphate buffer, were dialyzed against isotonic phosphate buffer of pH 7·4 using Spectrapor 2 membrane. The protein binding of vancomycin to 0·08 per cent AAG was dependent on vancomycin concentrations; the values ranged from 21·1 per cent at the vancomycin concentration of 20 μg ml−1 to 5·30 per cent at 2400 μg ml−1. However, binding to 4 per cent HSA was relatively constant, 8·79 ± 2·43 per cent over a vancomycin concentration range of 20–2400 μg ml−1. The values to 4 per cent HSA alone and 0·08 per cent AAG alone did not predict the greater binding of vancomycin in the presence of both proteins, especially at higher concentrations of vancomycin; the values to 4 per cent HSA with 0·08 per cent AAG were constant, 26·3 ± 3·74 per cent, at the vancomycin concentration range of 20–2400 μg ml−1. This suggested an interaction between the proteins, which resulted in enhanced binding of vancomycin. The protein binding of vancomycin to 4 per cent HSA with 0·08 per cent AAG was not influenced by the different incubation temperatures (4°, 22°, and 37°), quantities of heparin (up to 40 units ml−1) or AAG (up to 0·16 per cent), or buffers (isotonic phosphate buffer of pH 7·4, phosphate buffer of pH 7·4 and 0·9 per cent NaCl solution) at the vancomycin concentration of 80 μg ml−1. Vancomycin was found to be stable in human serum albumin or in isotonic phosphate buffer of pH 7·4.
Effect of dehydration on the disposition kinetics of erythromycin in rabbits
Authors: Ahmad M. , Niazi S. K. , Ahmad T. , Muzaffar N. A. , Nawaz M.
Published: October 2006

The effect of water deprivation on the physiologic, biochemical, and disposition parameters of erythromycin was investigated in rabbits. The packed cell volume, plasma glucose, and total lipid concentration increased significantly in dehydration. The pharmacokinetic parameters of erythromycin after intravenous administration also changed, suggesting a need for monitoring toxicity of erythromycin in the water‐deprived population.
Pharmacokinetics of the antidepressant levoprotiline after intravenous and peroral administration in healthy volunteers
Authors: Kaiser G. , Ackermann R. , Dieterle W. , Reimann I. W. , Bieck P. R.
Published: October 2006

To investigate the pharmacokinetics and the disposition of levoprotiline after i.v. and p.o. administration and to assess the absolute bioavailability, 12 healthy volunteers (11 women, 1 man) were given a 10 min i.v. infusion of 15 mg and a p.o. dose of 75 mg in a two‐way crossover study. Blood and urine samples were collected after each dose. Unchanged levoprotiline and the sum of unchanged and glucuronidated levoprotiline (=total levoprotiline) were determined by a specific gas chromatographic‐mass spectrometric method.

Intravenous levoprotiline was rapidly and extensively distributed into extravascular sites of the body; the steady‐state volume of distribution was 18·81 kg−1. The elimination of levoprotiline from blood was independent of the dosing route, the half‐life being 18·8h. Only 1·8 and 0·6 per cent of the i.v. and p.o. dose, respectively, were excreted unchanged in the urine, whereas 57 per cent of each dose were renally excreted as total levoprotiline.

The absolute bioavailability of p.o. levoprotiline was 40 per cent. About 60 per cent of the dose was subject to a first‐pass effect in the liver. The systemic blood clearance of levoprotiline, determined after i.v. dosing, was 885 ml min−1, the renal blood clearance after i.v. and p.o. dosing was only 16·0 and 14·2 ml min−1, respectively. Presystemic and systemic clearance of levoprotiline occurred predominantly by direct glucuronidation.
Prediction of netilmicin disposition in neonates
Authors: Darwish M. , Batayneh M. , Jenkins J. , Scott M. , Collier P. S. , McElnay J. C.
Published: October 2006

Multiple regression analyses of data from 33 neonates who received netilmicin therapy showed that concurrent treatment with other drugs (Drg), creatinine clearance (CLcr), gestational age (GA), and an apgar score of less than 6 at 1 min (Agl') were significant determinants of netilmicin clearance. Apparent volume of distribution was significantly affected by postnatal age (PNA), gender, the presence of ascites and/or oedema (A/O), and whether or not the neonate was small for gestational age (SGA). The following formulae were obtained: magnified image.

The regression formulae were shown to predict netilmicin plasma concentrations with good precision and a non‐significant bias in a further 15 neonates studied prospectively.
Pharmacokinetics of nitroglycerin and its metabolites after administration of sustained‐release tablets
Authors: Kwon Hae‐Ryun , Green Preston , Curry Stephen H.
Published: October 2006

Nitroglycerin was administered to eight healthy volunteers in the form of sublingual tablets, oral sustained‐release tablets, and an oral solution. Blood samples were collected for measurement of nitroglycerin and its two isomeric glyceryl dinitrate metabolites. Blood pressure and pulse rate were monitored; subjective evaluations of headache, dizziness, facial flushing, skin irritation, and gastrointestinal upset were made. Nitroglycerin itself was virtually undetectable after the solution and tablet preparations; the metabolites were consistently detectable from a few minutes after dosing to 24h later. Mean total (nitroglycerin plus metabolite) concentrations were comparable in the 15 min following sublingual administration, and the 8h following tablet administration. The relative bioavailability of the tablets in comparison with the oral solution was 70 per cent based on metabolite concentrations. Nitroglycerin sustained‐release tablets appear to exert their beneficial effects in the prolonged prophylaxis of angina through active metabolites.
In vitro reduction of rhein anthraquinone to rhein anthrone by rat cecal microflora and some intestinal bacterial strains
Authors: de Witte P. , van Hoestenberghe A. , Eyssen H.
Published: October 2006

After in vitro incubation of cecal content from CVL or gnotobiotic rats with rhein anthraquinone (1 mg g−1) for 18 h at 37°, the anthraquinone was converted to rhein anthrone for 23·5 (SD ± 3·4) per cent and 19·4 (±4·7) per cent, respectively. Liquid cultures of some strictly anaerobic fecal bacteria of man and mouse incubated with rhein anthraquinone (62·5 μg ml−1) for 48 h at 37°, revealed only smail amounts of reduced substance. Although the underlying mechanisms of the differences in both conditions remain unclear, the experimental data accentuate the need for using cecal content when exploring the in vitro metabolism of anthranoids by the intestinal microflora. The conversion was chemically proven by derivatization of the anthrone with 4‐nitroso‐N‐N‐dimethylaniline in pyridine, followed by hydrolysis and identification of the released anthranoid by mass spectrometry. The in vitro reduction capacity of the cecal content of CVL rats was drastically decreased by oral administration to rats of different combinations of neomycin sulfate, metronidazole, bacitracin and Na‐penicillin G. In these cases the conversion ranked between 0·2 per cent and 5·2 per cent the first day after administration. It is concluded that rhein anthraquinone in cecal content is reduced to the highly reactive and labile rhein anthrone, which accounts for the in vivo disappearance of dihydroxy‐anthranoid equivalents in routine analysis after oral administration of anthraquinones to experimental animals.
Pharmacokinetics of ketotiffn after oral administration to healthy male subjects
Authors: Grahnén A. , Lönnebo A. , Beck O. , Eckernäs S‐Å , Dahlström B. , Lindström B.
Published: October 2006

The pharmacokinetics of 2 mg ketotifen from four different oral dosage forms were examined in two randomized, balanced cross‐over studies. Forty healthy male subjects participated. Each of 20 subjects received two capsule formulations and each of the other 20 subjects received two syrup formulations. Ketotifen concentrations in plasma were determined by a modified GC—MS method. The limit of quantitation was 40 pg ml−1. Inter‐day precision and accuracy calculated from quality control samples were 16·3 per cent (−1·9 per cent), 19·8 per cent (+4·5 per cent) and 23·6 per cent (+ 5·9 per cent) at plasma concentration levels of 86 (n = 18), 215 (n = 19) and 343 (n = 18) pg ml−1, respectively. Ketotifen was rapidly absorbed from all dosage forms reaching Cmax in the order of 400 pg ml−1 after the syrup formulations and 300 pg ml−1 after the capsule formulations within 2 to 4 h. The syrup formulations showed a significantly more rapid rate of absorption as assessed by Tmax. No significant differences in extent of absorption between dosage forms were observed. The terminal elimination half‐life of ketotifen varied between subjects from 7 to 27 hours with a mean of about 12 h. The minor pharmacokinetic difference between dosage forms observed in this study is unlikely to be of clinical significance.
Absorption and disposition of fluvastatin, an inhibitor of HMG‐CoA reductase, in the rabbit
Authors: Tse F. L. S. , Labbadia D.
Published: October 2006

The absorption and disposition of fluvastatin have been studied in the female rabbit. In naive rabbits receiving a single oral dose (1 mg kg−1) of [3H] fluvastatin, absorption was rapid and amounted to c. 90 per cent compared with an intravenous reference dose. The drug was subject to considerable first‐pass effect, its absolute bioavailability being 46 per cent. The steady‐state volume of distribution of fluvastatin was 0·29±0·04 1 kg−1 while the total body clearance was 0·33±0·05 1 h−1 kg−1. The administered radioactivity was excreted predominantly in feces, with the renal pathway accounting for 28±4 per cent of the oral dose and 32±3 per cent of the intravenous dose. In pregnant rabbits on a multiple oral dosing regimen, 1 mg kg−1 day−1 beginning day 6 post‐conception (p.c.), steady‐state concentrations in maternal blood and tissues were achieved within 5 days. The concentrations in the reproductive organs were c. 25–50 per cent of that in maternal blood while those in the kidneys and liver were considerably higher. In contrast, radioactivity levels in the fetuses and amniotic fluid decreased significantly during repeated drug administration. The fetus: placenta and amniotic fluid: placenta concentration ratios declined from 0·92 and 0·97, respectively, on day 10 p.c. to 0·10 and 0·04, respectively, on day 18 p.c., indicating a limited transfer of fluvastatin and/or its metabolite(s) across the placenta at the later stage of pregnancy. After cessation of dosing, radioactivity levels in all tissues and fluids showed a progressive and nearly parallel, decline, suggesting no tissue retention of the drug.
Effect of basic drugs on the hepatic uptake of ouabain by sinusoidal plasma membrane vesicles isolated from rat liver
Authors: Okudaira Kazuho , Yachi Kiyoto , Sawada Yasufumi , Sugiyama Yuichi , Iga Tatsuji , Hanano Manabu
Published: October 2006

Although antiarrhythmic drugs are used to treat digitalis‐induced cardiac disorders, some of these drugs have been reported to increase the serum digoxin concentration in patients, causing the severe side‐effects. We have previously shown that many basic drugs including antiarrhythmic drugs inhibited the hepatic uptake of cardiac glycosides into isolated rat hepatocytes, which could be a cause for the increased serum digoxin concentration. The present study was designed to examine the mechanism of this inhibition using isolated rat sinusoidal plasma membrane vesicles. The effect of nine basic drugs (dipyridamole, nifedipine, verapamil, chlorpromazine, lidocaine, quinidine, ajmaline, disopyramide, and propranolol) on the uptake of ouabain was studied. Quinidine reduced the initial uptake rate of ouabain (30 s) while it did not change the uptake of ouabain in an equilibrium condition (30 min). Other basic drugs, such as verapamil, dipyridamole, and nifedipine also significantly reduced the initial uptake rate of ouabain. These basic drugs had no effect on the membrane fluidity. The inhibitory effects on the vesicular uptake were significantly correlated with the inhibitory effects on ouabain uptake by the isolated rat hepatocytes. These findings may suggest that the mechanism of the inhibition involves the inhibition of the transport process via the sinusoidal plasma membrane.
Drugs and the liver. Part III: Ageing of the liver and the metabolism of drugs
Authors: Woodhouse Ken
Published: October 2006

The clearance of many drugs by the liver is reduced in the elderly, and this accounts, at least in part, for the greater frequency of adverse drug reactions in this population.

Ageing in experimental animals is accompanied by a decline in the activities of certain microsomal monooxygenase enzymes; this has been said to be the reason for decreased drug elimination. However, recent data suggests that this is probably not the case in humans. Reduced size and blood flow are important features of the ageing liver, and probably account for most of the age‐related changes in drug metabolism. Major decrements in hepatic function do occur in frail elderly individuals, although the mechanisms underlying this are at present unclear.

Future studies of drug metabolism and ageing must carefully define patient groups to allow full interpretation of data.
Effect of indomethacin on the pharmacokinetics of methotrexate in rabbits
Authors: Najjar Tawfeeg A. O. , Morad Abdel Rehim M. , Khan Rao Muzaffar A.
Published: October 2006

The interaction between indomethacin (IND) and methotrexate (MTX) was investigated in rabbits. The study was designed so as to evaluate the effect of IND (1 mg h−1) during a continuous MTX infusion (1·2 mg kg−1) over 240 min. IND was injected i.v. at hourly intervals after a steady state MTX concentration had been established. Plasma MTX concentration before and after IND did not differ significantly (p>0·05). The elimination half‐life (t1/2β) calculated during the washout interval (mean ± SD) was 47·4 ± 21·5 min which is close to that calculated in a reference group of rabbits. This excludes the possibility of delayed elimination as responsible for this toxicity. The toxicity of this combination was confirmed despite the absence of significant pharmacokinetic changes. It is possible that the toxic interaction was caused by enhanced cytotoxic effect of MTX.
Effect of food and relative bioavailability following single doses of diclofenac 150mg hydrogel bead (HGB) capsules in healthy humans
Authors: Thakker K. M. , Mangat S. , Wagner W. , Castellana J. , Kochak G. M.
Published: October 2006

The effect of food on the bioavailabilty of diclofenac from a 150mg diclofenac hydrogel bead (HGB) capsule was evaluated in 12 healthy male subjects in a fed and fasted state. Additionally, the fasting bioavailability of diclofenac from a 150mg diclofenac HGB capsule relative to diclofenac sodium in buffered aqueous solution was evaluated in these same 12 subjects. The study was designed as an open‐label, randomized, single‐dose, 3×3 Latin‐square crossover trial balanced for residual effects. A 2‐week washout period was maintained between treatments. Blood samples were collected at frequent intervals over a 24‐h period with plasma being separated and analyzed for diclofenac using a validated HPLC method.

The administration of the 150mg diclofenac HGB capsule dose within 30 min following a standardized breakfast minimally affected the bioavailability of diclofenac relative to administration under fasted conditions (7 per cent decrease in AUC(0‐24), p>0·05). There was, however, a 38 per cent decrease (p<0·05) in the Cmax and a three‐fold increase (p<0·05) in Tmax for the fed HGB capsule administration.

Under fasted conditions, significant differences in mean pharmacokinetic parameters were found between the 150mg diclofenac HGB capsule and diclofenac sodium in buffered aqueous solution. The extent of availability of diclofenac from the HGB capsule was only 59 per cent relative to that from the solution (p<0·05). There was a 92 per cent decrease in the maximum plasma diclofenac concentration (Cmax, p<0·05) and an eight‐fold increase (p<0·05) in the median time required to reach this maximum level (Tmax) following HGB capsule administration.

In conclusion, post‐prandial administration of the 150mg diclofenac HGB capsule resulted in a minimal decrease in bioavailability. The oral bioavailability of the diclofenac sodium in 150 mg diclofenac HGB capsules is significantly decreased relative to that of diclofenac sodium in solution.
‘In vitro’ action of histamine and cimetidine on amylase secretion in the rat pancreas
Authors: Murillo Luis Jiménez , Torre‐Cisneros Julián , Blanco‐Molina Angeles , López‐Miranda José , de la Puebla Rafael Angel Fernández , Pérez‐Jiménez Francisco
Published: October 2006

We report here the effect of histamine on amylase secretion in isolated lobules from the rat pancreas. Different concentrations of histamine increased amylase secretion, while the stimulatory effect was reduced by cimetidine although not by chlorpheniramine. These findings suggest that pancreatic lobules have H2 receptors. On the other hand, bethanechol induced a stimulatory effect on pancreatic lobules that was inhibited by cimetidine. Vibrio cholerae toxin stimulated amylase secretion, but this effect was not reduced by cimetidine. Cimetidine may thus block the stimulated amylase secretion interfering with the Ca2+ messenger system.
Prediction of the volume of distribution of 7‐hydroxycoumarin in man from in vitro and ex vivo data obtained in rat
Authors: Ritschel W. A. , Johnson R. D. , Vachharajani N. N. , Hussain A. S.
Published: October 2006

The essential parameter to estimate the first dose size of a drug in man is the volume of distribution. For a drug that has never been used in man before, estimates of the volume of distribution can only be obtained from animals and in vitro data. The purpose of this study was to compare various approaches presented in the literature for predicting the volume of distribution at steady state (VSS) and the terminal phase volume of distribution (Vdβ) in man. A lipophilic active metabolite of coumarin, 7‐hydroxycoumarin (7OHC), was selected for this investigation. This compound is extensively metabolized in both the central and peripheral compartments. Of the six methods evaluated, only an empirical allometric approach yielded a reasonable estimate of VSS. All methods underestimated VSS and none of the applicable methods were able to predict Vdβ. The reason for this discrepancy may be due to the fact that the calculation of Kss in man was done assuming elimination from the central compartment.
Influence of probenecid and paracetamol (acetaminophen) on zidovudine glucuronidation in human liver in vitro
Authors: Kamali F. , Rawlins M. D.
Published: October 2006

The effects of probenecid and paracetamol on zidovudine glucuronidation were investigated, in vitro, using human liver microsomal preparations. The presence of probenecid in the incubation medium significantly reduced the maximum reaction velocity for zidovudine glucuronide formation by more than 60 per cent, and the Km was reduced by 47 per cent, suggesting an uncompetitive inhibition of zidovudine glucuronidation. In contrast, paracetamol had no significant effect on zidovudine glucuronidation. The maximum reaction velocity for zidovudine glucuronide formation and the Km were unchanged when paracetamol (5 mM) was present in the incubation medium. The effects of probenecid and paracetamol on zidovudine metabolism in vitro correlates closely with those observed in vivo. The in vitro system of human liver microsomes may have a useful role in predicting the possible interaction of other drugs with zidovudine metabolism.
Pharmacokinetics and metabolism of codeine in humans
Authors: Vree Tom B. , Wissen Corrien P. W. G. M. Verwey‐Van
Published: October 2006

Codeine (30 mg phosphate) was metabolized by eight human volunteers to the following six metabolites: codeine‐6‐glucuronide 81·0 ± 9·3 per cent, norcodeine 2·16 ± 1·44 per cent, morphine 0·56 ± 0·39 per cent, morphine‐3‐glucuronide 2·10 ± 1·24 per cent, morphine‐6‐glucuronide 0·80 ± 0·63 per cent, and normorphine 2·44 ± 2·42 per cent. Two out of eight volunteers were unable to O‐dealkylate codeine into morphine and lack therefore the cytochrome P450 IID6 isoenzyme. The half‐life of codeine was 1·47 ± 0·32 h, that of codeine‐6‐glucuronide 2·75 ± 0·79 h, and that of morphine‐3‐glucuronide 1·71 ± 0·51 h. The systemic clearance of codeine was 2280 ± 840 ml min−1, the renal clearance of codeine was 93·8 ± 29·8 ml min−1, and that of codeine‐6‐glucuronide was 122 ± 39·2 ml min−1. The plasma AUC of codeine‐6‐glucuronide is approximately 10 times higher than that of codeine. Protein binding of codeine and codeine‐6‐glucuronide in vivo was 56·1 ± 2·5 per cent and 34·0 ± 3·6 per cent, respectively. The in vitro protein binding of norcodeine was 23·5 ± 2·9 per cent; of morphine, 46·5 ± 2·4 per cent; of normorphine, 23·5 ± 3·5 per cent; of morphine‐3‐glucuronide, 27·0 · 0·8 per cent; and of morphine‐6‐glucuronide, 36·7 ± 3·8 per cent.
Extended least squares curve fitting: A comparison of SIPHAR and MKMODEL
Authors: Cockshott Ian D. , Haywood John
Published: October 2006

SIPHAR and MKMODEL in their extended least squares modes have been compared when fitting a triexponential declining function to simulated data. The data were simulated on SAS incorporating normally distributed random error, having coefficients of variation (CV) of 5, 10, 15, and 25 per cent. At each error level 100 data sets, consisting of 21 data pairs, were simulated. Non‐parametric tests were used to compare the accuracy and precision of the estimates produced by the packages. The comparison was repeated with two different sets of exponent values incorporating error at the 15 per cent level. MKMODEL was also compared to ELSFIT and ELSMOS at the same error level. SIPHAR was consistently less accurate and less precise than MKMODEL in estimating the structural model parameters. SIPHAR was also sensitive to the concentration units used for the input data. Estimates of the variance model power produced by SIPHAR were very variable while those from MKMODEL covered a much tighter range. For both packages there was generally a linear increase in the CV on each mean parameter estimate with increase in the CV on the error model. Good agreement was observed between MKMODEL, ELSFIT, and ELSMOS. The presence of an additive constant in the variance model used in SIPHAR was shown to be responsible for its poorer accuracy and precision.
Bioavailability of lithium from lithium citrate syrup versus conventional lithium carbonate tablets
Authors: Guelen P. J. M. , Janssen T. J. , de Witte T. C. M. , Vree T. B. , Benson K.
Published: October 2006

The bioavailability of lithium citrate syrup was compared with that of regular lithium carbonate tablets in 18 healthy male human volunteers. Blood samples were collected up to 48 h after dosing. Lithium serum concentrations were determined by means of AAS. The absorption rate following oral administration of the syrup was greater (tmax 0·8 h) than following administration of regular tablets (tmax 1·4 h). Maximum lithium serum concentrations, however, were only about 10 per cent higher after syrup dosing and serum concentrations resulting from syrup and tablets were almost superimposable from 2 h after dosing. The terminal half‐life of lithium was found to be 22 h after syrup as well as after tablet dosing. No side‐effects were observed during the study. The bioavailability of lithium from syrup relative to tablets was found to be bioequivalent with respect to the maximum lithium serum concentration and the extent of drug absorption (AUC).
Effect of congestive heart failure on clentiazem pharmacokinetics in a dog model
Authors: K.‐Laflamme Annik , Caillé Gilles , Cardinal René , Croteau Daniel , Lamoureux Claudette , Lambert Chantal
Published: October 2006

Clentiazem, 8‐chloro diltiazem, is a calcium channel blocker currently undergoing evaluation for the treatment of stable angina and hypertension. As patients with ischaemic disorders often present some degree of heart failure, the aim of this study was to investigate the effect of congestive heart failure on clentiazem (200 μg kg−1, i.v. bolus) pharmacokinetics in a canine model. Congestive heart failure was induced in six dogs by rapid ventricular pacing (240 beats min−1) for 3–5 weeks. Clentiazem pharmacokinetics was studied in each dog under the control condition and after the development of clinical signs of heart failure (ascites, dyspnea, fatigue). Blood samples were collected up to 480 min post‐dose. Clentiazem plasma concentrations were determined by high performance liquid chromatography. The area under the plasma concentration versus time curves (AUC0−∞) was significantly increased in congestive heart failure dogs (8·8 ± 1·6 vs 21·8 ± 1·4 μg min ml−1) (mean ± SEM). These changes were related to a reduction of the volume of distribution of the central compartment (0·9 ± 0·1 vs 0·2 ± 0·1 1kg−1) and total body clearance (1·9 ± 0·4 vs 0·7 ± 0·2 1h−1 kg−1). It is concluded that, in our model, congestive heart failure significantly modifies clentiazem disposition. These results suggest that caution should be exercised when clentiazem is given to patients with a low ejection fraction and a compromised cardiac function. Reduced loading and maintenance doses might be recommended in patients with severe congestive heart failure.
The effects of chronic oral diltiazem and cimetidine dosing on the pharmacokinetics and negative dromotropic action of intravenous and oral diltiazem in the dog
Authors: Maskasame Chaiyasit , Lankford Susan , Bai Stephen A.
Published: October 2006

The kinetics and negative dromotropic action of intravenous (1 mg kg−1) and oral (5 mg kg−1) diltiazem were studied in dogs after acute doses, after treatment for 3 days with oral diltiazem (5 mg kg−1, t.i.d.), and after 3 days' treatment with oral diltiazem (5 mg kg−1 t.i.d.) and cimetidine (200 mg t.i.d.). Plasma concentrations of diltiazem and two of its metabolites, desacetyldiltiazem and desmethyldiltiazem were measured by HPLC. Chronic oral dosing significantly lowered both the systemic and oral clearance of diltiazem, with no changes in either the volume of distribution or blood binding of diltiazem. Cimetidine treatment resulted in a significant reduction in diltiazem oral clearance from chronic control with no effect on its systemic clearance. The AUCs of both metabolites increased by greater than threefold from acute to chronic oral dosing; however, the ratio of each metabolite's AUC to that of diltiazem AUC was not significantly altered. Cimetidine treatment significantly lowered these ratios. The negative dromotropic potency of diltiazem after the acute oral dose was three times greater than that after intravenous or chronic control dosing. Cimetidine treatment resulted in further lowering chronic oral diltiazem potency. These data indicate that the disposition and negative dromotropic action of diltiazem is dependent both on the route of administration and the duration of treatment, and can be altered by co‐administration with cimetidine.
Simultaneous monitoring of bemoradan pharmacokinetics and hemodynamics in mongrel dogs
Authors: Huang Shiew‐Mei , Falotico Robert , Haertlein Barbara , Smith Ian L.
Published: October 2006

This study was designed to determine the relationship between the hemodynamic responses to bemoradan, a novel cardiotonic agent, and its plasma levels after single administration of an oral dose or a 15 minute i.v. infusion to mongrel dogs, and to demonstrate that the clinical capsule formulation of bemoradan elicits a pharmacological response in the dog. Four conscious, instrumented mongrel dogs received each of four bemoradan treatments (30μg kg−1 i.v., 100μ kg−1 i.v., 100μ kg−1 suspension p.o., or 1 mg capsule p.o.) in a Latin square cross‐over design. Plasma levels of bemoradan up to 24 h post‐dosing were determined by HPLC. Cardiac contractility (dP/dt), heart rate, and arterial blood pressure were continuously monitored for 8 h and again at 24 h. Results of the study indicate that there was a significant correlation between bemoradan plasma levels and dP/dt. The 1 mg clinical capsule formulation was well absorbed when compared to an oral suspension and an i.v. dose. Peak increases in dP/dt of 64 per cent at 15 min for the suspension and 53 per cent at 1 h for the capsule were observed.
Pharmacokinetics of alfuzosin after single oral administration to healthy volunteers, of three different doses
Authors: Salva P. , Bianchetti G. , Morselli P. , Garcia‐Teresa G. , Costa J.
Published: October 2006

The aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2·5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2β) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1–5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2·5, and 5 mg were, respectively: tmax (h) 1·5±0·3, 1·1±0·2, 1·3±0·1; Cmax (ng ml−1) 2·6±0·3, 9·4±1·2, 13·5±1·0; AUC (ng ml−1 h) 17·7±2·9, 51·7±7·1, 99·0±14·1; t1/2 (h) 3·7±0·4, 3·9±0·2, 3·8±0·3. Cmax (corrected by the dose) obtained after 2·5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2·5 mg and 4 volunteers of 12 after 5 mg.
Disposition kinetics of 7,12‐dimethylbenz(a)anthracene in rats
Authors: Niazi Sarfaraz K. , Hussain Musarrat
Published: October 2006

One of the most potent carcinogens is 7,12‐dimethylbenz(a)anthracene (7,12‐DMBA), which is used routinely to conduct studies to evaluate carcinogen inhibitors. Its pharmacokinetics have not been reported in the literature. In view of its significant effects on drug metabolizing enzymes and clearance mechanisms, it is important to know its disposition characteristics. In this study, we monitored the disposition characteristics of 7,12‐DMBA in rats as a function of dose range commonly used in carcinogenesis studies. A mean residence time of 40–55 min was observed; the total body clearance ranged from 8–13 1 kg−1. No effect of dose was observed on the pharmacokinetic parameters. This suggests that the dose‐dependent effects of 7,12‐DMBA carcinogenesis are related to its transient disposition characteristics.
Immunosuppressive effect of cyclosporine in the hyperlipidemic rat model
Authors: Luke David R.
Published: October 2006

The immunosuppressive effects of 2·5 (n = 6) and 5 mg kg−1 day−1 (n = 7) of cyclosporine (CSA) given intravenously for 9 days to the immunized, hyperlipidemic Zucker rat model were compared with drug‐free animals (n = 6) and lean litter‐mates given 0 (n = 6), 5 (n = 6), and 10 mg kg−1 day−1 (n = 8) of CSA. Thus, based on body weights, both obese rats and lean litter‐mates received total doses of 0, 1, and 2 mg of CSA. No significant differences in percent change in baseline body weight were found; in contrast, spleen weights were markedly greater in treated animals compared with controls. Serum cholesterol, triglycerides, and lipoprotein levels of obese rats were significantly greater than values found in lean litter‐mates. CSA concentrations in whole blood, serum, and the lipoprotein fractions obtained 4h after the final dose were greater in obese rats compared with lean litter‐mates. Immunosuppressive activity, as assessed by ex vivo T‐lymphocyte proliferation assay, was equivocal between all rats given CSA, independent of dose and obesity, and significantly greater than control animals. Whereas serum CSA levels were correlated to cholesterol levels (r = 0·95, p ± 0·0001), there were no significant correlations with immunosuppressive activity. The present data suggest that increased binding of CSA to lipoproteins in the vascular compartment does not significantly impact on its immunosuppressive activity.
Nonlinear pharmacokinetics of hepatobiliary transport of rose bengal in rats after iv bolus administration with varying doses
Authors: Wang Huan Kui , Miyachi Seiji , Yamazaki Masayo , Sawada Yasufumi , Chung Youn Bok , Iga Tatsuji , Hanano Manabu , Sugiyama Yuichi
Published: October 2006

To investigate the nonlinear kinetics in the hepatobiliary transport of rose bengal (RB), the time profiles of plasma concentration and biliary excretion rate after its i.v. administration at various doses were measured in rats. The total body clearance decreased remarkably with increased dose. The hepatic uptake clearance also showed a similar dose dependency, and saturation of hepatic uptake at least partly accounts for the dose‐dependent change in total body clearance. The peak biliary excretion rate approached the transport maximum (approximately 150 nmol min−1 kg−1) with increased dose. To further clarify which process in RB hepatobiliary transport has nonlinearity, we analysed thus obtained data based on a three‐compartment model. The hepatic uptake and sequestration rate constants decreased remarkably with increased dose. The initial hepatic uptake rates assessed from the plasma disappearance rate during the early phase fit well to the Michaelis‐Menten equation with a saturable and a nonsaturable component. The maximum uptake velocity and Michaelis constant were 4·7 μmol min−1 kg−1 and 360 μM, respectively. That hepatic uptake has a much higher capacity (about 30 fold) than biliary excretion suggests that biliary excretion can be a rate‐determining process in the overall hepatobiliary transport of RB. We conclude that the saturation of both hepatic uptake and biliary excretion could be the main causes for the nonlinear pharmacokinetics of hepatobiliary transport of RB.
Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid
Authors: Hadad Salim , Vree Tom B. , Van Der Kleijn Eppo , Bialer Meir
Published: October 2006

The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4‐butanediol divaiproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4‐butanediol.
A method for calculating the mean absorption time of drugs undergoing reversible and first‐pass metabolism
Authors: Cheng Haiyung , Shum Linyee
Published: October 2006

A method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.
Inhibition of acetaminophen and lorazepam glucuronidation in vitro by probenecid
Authors: Von Moltke Lisa L. , Manis Melanie , Harmatz Jerold S. , Poorman Roger , Greenblatt David J.
Published: October 2006

The effect of probenecid on glucuronidation of acetaminophen and lorazepam in hepatic microsomes from various species was studied to see if in vitro results were consistent with previous in vivo observations. Mouse, rat, and human microsomes were incubated with acetaminophen and probenecid while monkey microsomes were incubated with lorazepam and probenecid. Glucuronidation rates in all species varied with substrate, protein, and detergent concentrations. Mice exhibited faster rates of glucuronidation than rats or humans. All species showed inhibition of glucuronidation of acetaminophen or lorazepam when probenecid was added. Analysis suggested competitive inhibition. Thus, in vitro studies support in vivo results and confirm that the inhibition takes place at the hepatic level.