bluuebunny/crossref_metadata_2025 huggingface dataset:
Cocaine disposition in discrete regions of rat brain
Authors: Javaid J. I. , Davis J. M.
Published: October 2006

It has been proposed that various effects of psychoactive drugs on the central nervous system may be related to the capacity of the drug to selectively concentrate in specific regions of the brain. In rat brain, cocaine effects on striatal and nucleus accumbens dopaminergic systems show quantitative differences. However, the disposition of cocaine in various brain regions has not been reported. In the present studies we examined the cocaine concentrations over time in serum and discrete brain regions of the rat after single intraperitoneal (i.p.) injection. At different time points (5, 10, 20, 30, 60, 120, and 240 min) after i.p. injection of cocaine hydrochloride (10 mg kg−1, free base) the rats were decapitated and cocaine in serum and various brain regions was quantitated by a specific gas liquid chromatographic method. There was large inter‐individual variability in different rats at each time‐point. The disposition pattern of cocaine in rats after i.p. administration was similar to that observed in humans after intranasal administration. Initial absorption rate was rapid and, on average, the peak levels of cocaine were achieved in 10 min. The cocaine levels remained relatively high over the next 50 min indicating continual absorption, and then declined with a rate such that the levels 4 h after cocaine administration were undetectable in most of the animals. The overall changes in cocaine levels in various brain regions paralleled the serum concentrations. The area under the cocaine concentration‐time curve (AUC) revealed more than three‐fold differences in cocaine accumulation in various brain regions. This unequal disposition of cocaine may be responsible in part for differential biochemical effects in different brain regions.
Dual effect of valproic acid on the pharmacokinetics of phenytoin
Authors: Lai Ming‐Liang , Huang Jin‐Ding
Published: October 2006

To evaluate the effects of valproic acid on the disposition of phenytoin, a single dose of 600 mg valproic acid and multiple doses of valproic acid (200 mg four times a day for 5 days) were administered together with a single oral dose of 600 mg phenytoin to 12 young male volunteers. Fraction of unbound phenytoin and the area under curve (AUC) of the total and unbound phenytoin in plasma were compared with the control phase in which only 600 mg phenytoin was given. Valproic acid increased the unbound fraction of phenytoin in both single‐ and multiple‐dose studies by 15 per cent and 41 per cent, respectively. Single‐dose valproic acid increased the total AUC of phenytoin by 11 per cent. Multiple‐dose valproic acid decreased the total AUC by 7 per cent. Single‐and multiple‐dose valproic acid increased the unbound AUC by 25 per cent and 18 per cent, respectively, probably due to the inhibition on the metabolizing enzymes. We concluded that there are at least two mechanisms involved in valproic acid‐phenytoin interaction. Whereas valproic acid displacing phenytoin on the plasma protein decreased the total drug concentration of phenytoin, the enzyme inhibition by valproic acid increased both the total and unbound concentration of phenytoin. The two conflicting mechanisms may result in different effects on the total plasma concentration of phenytoin. Therapeutic drug monitoring based on the total concentration of phenytoin may be misleading when valproic acid is co‐administered.
Influence of food intake on the pharmacokinetics of a sustained release formulation of sodium valproate
Authors: Royer‐Morrot Marie‐Jose , Zhiri Azzedine , Jacob Francine , Necciari Jose , Lascombes Francoise , Royer Rene Jean
Published: October 2006

The effect of food intake on the pharmacokinetics of DEPAKINE® CHRONO 500 mg (Sanofi, France), a sustained release formulation containing 333 mg sodium valproate and 145 mg valproic acid, was studied in 12 young healthy female volunteers. Relative to fasting conditions (F), when the tablet was given at the midpoint of the breakfast (NF), the maximum concentration (F: 34.6 ± 8.9 μg ml−1 and NF: 40.9 ± 7.3 μg ml−1; p = 0.014) and the mean cumulative amount absorbed up to time 6 h (F: 76.3 ± 11.8% and NF: 90 ± 10.4%; p = 0.0099) were significantly increased. Nevertheless, the extent of absorption (F: 46.7 ± 9.9 mg l−1; NF: 48 ± 7.7 mg l−1) was not significantly affected. There was no change in the area under the curve (1129 μg.h ml−1), in the mean residence time (28 h), or in the elimination half‐life (16 h). On the basis of this study, the question as to whether DEPAKINE® CHRONO should be administered to subjects in the fasting or non‐fasting state would not appear to be a major consideration when deciding on the regimen.
Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to spontaneously hypertensive rats and DOCA‐salt induced hypertensive rats
Authors: Han Kye S. , Lee Sun H. , Lee Myung G. , Kim Nak D.
Published: October 2006

The pharmacokinetics and pharmacodynamics of bumetanide were investigated after intravenous (i.v.) administration, 10 mg kg−1, and oral administration, 20 mg kg−1, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate‐salt induced hypertensive rats (DOCA‐salt rats). After i.v. administration, the pharmacokinetic and pharmacodynamic parameters of bumetanide did not vary significantly between SHRs and the control Wistar rats. Similar results were also shown between DOCA‐salt rats and the control Sprague‐Dawley (SD) rats. After oral administration, the AUC0–12 h decreased significantly (186 versus 335 μg min ml−1) in SHRs and this resulted in decreased F(15.4 versus 23.6 and 2.78 versus 5.76% using two equations) in SHRs when compared with the control Wistar rats, although none of the other pharmacokinetic parameters varied significantly between SHRs and Wistar rats. This effect seemed to be due to the decreased enterohepatic recirculation of bumetanide in SHRs: the amounts of both bumetanide and its glucuronide product, which are capable of enterohepatic recirculation, excreted in 8 h bile juice decreased significantly in SHRs (11.3 versus 37.4 μg as expressed in terms of bumetanide) when compared with Wistar rats. The pharmacodynamic parameters did not vary significantly between SHRs and Wistar rats after oral administration of bumetanide. The pharmacokinetic and pharmacodynamic parameters of bumetanide did not vary significantly between DOCA‐salt rats and SD rats after oral administration of the drug. The liver weights compared to body weight increased significantly in SHRs when compared with Wistar rats and the corresponding values for the kidney increased significantly in DOCA‐salt rats when compared with SD rats.
Intravenous verapamil kinetics in rats: Marked arteriovenous concentration difference and comparison with humans
Authors: Manitpisitkul Prasarn , Chiou Win L.
Published: October 2006

The pharmacokinetics of verapamil, a calcium channel blocker, were studied in male Sprague—Dawley rats following i.v. administration at a dose of 1 mg kg−1. Both arterial and venous blood were collected and the plasma drug concentrations were determined by reversed‐phase high‐performance liquid chromatography. Verapamil was distributed to the extravascular tissues very rapidly as indicated by the large Vdss (2.99±0.57 1 kg−1) and Vdβ (5.08 ± 0.541 kg−1). The apparent terminal plasma T1/2, MRTiv, and CLp were 1.59 ± 0.46, 1.26 ± 0.12 h, and 40.4 ± 9.73 ml min−1 kg−1, respectively. Marked arterial/venous differences were found with a considerable influence on the MRT and Vdss, and the terminal phase venous levels were higher than arterial levels by 103, 69, and 90%, respectively, for the three rats studied. The distribution of verapamil between plasma and erythrocytes occurred very rapidly and was identical in vitro and in vivo. The average blood to plasma and plasma to blood cell concentration ratios were 0.85 and 1.47, respectively. In contrast to propranolol, blood data rather than plasma data should be used to predict the hepatic extraction ratio of verapamil (0.87). The plasma protein binding of verapamil in humans (90%) and rats (95%) were quite similar and constant over the wide concentration range studied. A comparison of some pharmacokinetic parameters between rats and humans is presented and the potential shortcomings of using T1/2 or CLp and the advantage of using CLu (unbound plasma clearance) in interspecies scaling is also discussed.
Pharmacokinetics of oral L‐isoidide mononitrate in rats
Authors: Tzeng Tsang‐Bin , Fung Ho‐Leung
Published: October 2006

L‐isoidide mononitrate (L‐IIMN) is the most potent mononitrate vasodilator described so far in the literature. Since other mononitrates, such as isosorbide‐5‐mononitrate and isosorbide‐2‐mononitrate, have been shown not to be subject to first‐pass metabolism, we examined the pharmacokinetics of L‐IIMN after oral administration to determine whether this compound also exhibited this behavior. An oral dose of 2 mg kg−1 L‐IIMN dissolved in normal saline was given to seven rats. Absorption of L‐IIMN after dosing was rapid with an apparent absorption half‐life of 9.5 ± 3.6 min (mean ± SD). Plasma L‐IIMN concentrations peaked between 5 and 20 min after dosing and declined thereafter in an apparently monoexponential manner. The average elimination half‐life was 11.9±1.7 min (mean ± SD). Oral bioavailability was estimated to be about 50%. Thus, unlike the other mononitrates so far examined in the literature, L‐IIMN exhibits incomplete bioavailability. This pharmacokinetic behavior, however, is consistent with its faster systemic clearance compared to other organic mononitrates.
Kinetic analysis of tissue distribution of doxorubicin incorporated in liposomes in rats (II)
Authors: Harashima Hideyoshi , Midori Yukari , Ohshima Shunji , Yachi Kiyoto , Kikuchi Hiroshi , Kiwada Hiroshi
Published: October 2006

The objective of this study is to perform kinetic modelling of the tissue distribution of doxorubicin encapsulated into liposomes (L‐DXR), especially to the heart and liver. The release process of doxorubicin (DXR) from liposomes in blood was quantified by a release clearance. This parameter defines a release rate of DXR based on the concentration of L‐DXR in blood and was estimated from kinetic modelling of DXR distribution to the heart after L‐DXR administration. The distribution of free DXR to the heart was modelled separately. The experimental data for this modelling were reported previously (Harashima et al., Biopharm. Drug. Disposit., 13, 155–170 (1992)). This analysis provided a free DXR concentration profile as well as a release clearance of DXR after L‐DXR administration. There was a remarkable difference in the free DXR concentration in blood between free and liposomal administration. The area under the DXR curve in the heart was reduced by approximately one third from that for the first two hours after DXR administration by liposomal encapsulation, which could be the reason for reduced cardiac toxicity. In our previous report, the distribution of L‐DXR to the liver was shown to be explained by a sequentially linked two‐compartment model with efflux process. The validity of this efflux model was examined in this study by a repeated dose study. The apparent uptake clearance decreased with time and showed a second peak after the repeated dose, which justified the efflux model. These kinetic analyses give quantitative understanding of the effect of liposomal encapsulation on the tissue distribution of DXR.
Influence of albumin on isoprenaline and propranolol effects on isolated rat uterus
Authors: Morgan Denis J. , Richmond Barbara H. , Malta Errol
Published: October 2006

We investigated the effect of albumin (6%) on the (±)‐isoprenaline‐induced relaxation of strips of isolated rat uterus and its antagonism by (−)‐propranoioi. The mean isoprenaline EC50 in the presence of albumin was significantly less than that in the absence of albumin (geometric mean 1.94 ± 3.33 versus 3.21 ± 3.50 nM, respectively; n = 14; p = 0.006, paired t test). This indicates enhancement of isoprenaline activity by albumin which could not be explained by protein binding, as this would have reduced activity. Geometric mean control KB values for inhibition of isoprenaline by propranolol at 26.8 and 500 nM were 0.835 ± 1.68(n = 10) and 0.889 ± 1.60 nM (n = 34), respectively. In the presence of 6% albumin, KB for propranolol was increased significantly to 13.3 ± 1.8 nM (n = 27, p <0.001). Calculation of KB in terms of the measured propranolol unbound concentration of 26.8 nM, after taking into account the lower isoprenaline EC50 in the presence of albumin, yielded a mean value of 0.725 ± 1.86 nM, which was not significantly different from either control (p >0.05). Therefore, propranolol activity was as predicted by the unbound drug concentration in Contrast to isoprenaline activity. We conclude that albumin can alter in vitro drug activity by mechanisms in addition to the reduction of unbound drug concentration.
An estimate of the rate of direct drug diffusion from the surface of heart and kidney—implications for their representation as compartments
Authors: Huang Yi Fei , Upton Richard N.
Published: October 2006

In many regional pharmacokinetic experiments and models, the anatomical boundaries of the heart and kidney are intrinsically assumed to be barriers for drug diffusion such that these organs can be represented as one or more compartments. To test this, an experimental preparation was developed in which the heart and kidney of anaesthetized sheep were surrounded with 0.9% saline. The rate of drug diffusion from the surface of the organs into the saline was examined during constant‐rate i.v. drug infusions. It was found that the maximum clearances of lidocaine and procainamide into the pericardial saline were 10.3–11.6 and 0.6–2.1 ml min−1 respectively, and the values for the kidney were 0.3–0.6, 0.1–1.0 and 0.4–1.3 ml min−1, for lidocaine, procainamide, and meperidine respectively. These corresponded to calculated times of 4–481 min to reach the steady‐state saline concentration depending on the drug and the organ. The steadystate ratio of the saline concentrations over the arterial blood drug concentrations usually ranged from 0.5–1.0. It is concluded that drugs can rapidly enter regions of low or no perfusion surrounding these organs, and that the concept of treating the heart and kidney as compartments may not be valid in certain ‘worst‐case’ situations.
The structural barrier of absorptive mucosae: Site difference of the permeability of fluorescein isothiocyanate‐labelled dextran in rabbits
Authors: Hosoya Ken‐Ichi , Kubo Hiroyuki , Natsume Hideshi , Sugibayashi Kenji , Morimoto Yasunori , Yamashita Shinji
Published: October 2006

The permeability of fluorescein isothiocyanate‐labelled dextran (FD, M.W. 4400‐71 200) across nasal, buccal, duodenal, jejunal, ileal, colonic, and rectal mucosae excised from rabbits has been measured to estimate the structural barrier of absorptive mucosae using Ussing‐type diffusion chambers. The permeability coefficient of FD in all these mucosae decreased with increasing molecular weight. The rank order of FD permeability did not always correlate with the electrical resistance of the mucosae. Among components of the small intestine (duodenum, jejunum, ileum) and the large intestine (colon, rectum), however, the rank order of FD permeability corresponded to the magnitude of the electrical resistance in each instance; the upper colonic mucosa showed the highest permeability, especially in FD of low molecular weight, and permeability of the rectal mucosa was lowest except for the duodenal mucosa. The nasal mucosa showed the lowest electrical resistance and the highest permeability of those studied, suggesting that it has a leaky structural barrier.
Comparison of a new orally potent tripeptide HIV‐1 protease inhibitor (anti‐aids drug) based on pharmacokinetic characteristics in rats after intravenous and intraduodenal administrations
Authors: Kiriyama A. , Mimoto T. , Kisanuki S. , Kiso Y. , Takada K.
Published: October 2006

Recently, a series of KNI compounds such as KNI‐227 and KNI‐272 has been synthesized and shows potent and selective HIV‐1 protease inhibitory activity in vitro. In this study, we developed an HPLC assay system for KNI‐227 and KNI‐272 in rat plasma and examined the pharmacokinetic characteristics in rats after both intravenous (i.v.) and intraduodenal (i.d.) administrations to obtain the disposition characteristics and bioavailabilities of these new anti‐AIDS drugs. After i.v. administration of KNI‐227, 10.0mg kg−1, the mean terminal elimination half‐life, t1/2λz, was 0.808±0.161(SE)h, the total body clearance, CLtot, was 11.7±3.3 ml min−1 and the distribution volume at steady state (Vd,ss) was 1410.460 ml kg−1. On the other hand, after i.v. administration of KNI‐272, 10.0mg kg−1, t1/2λz was 2.86±0.78 h, CLtot was 15.3±1.4 ml min−1 and Vd,ss was 3440.670 ml kg−1. In the case of the i.d. administration of drugs, the mean peak plasma concentrations, Cmax, of KNI‐227 and KNI‐272 were 0.374±0.110μg ml−1 and 0.900±0.093 μg ml−1, respectively. The bioavailabilities (BA) of KNI‐227 and KNI‐272 to infinity, BA(0‐∞), were 5.90% and 42.3%, respectively. As compared with the lead compound, KNI‐174, the BA of KNI‐272 was improved about 10 times. Although the anti‐AIDS virus activity of these two drugs has not been investigated in vivo, KNI‐272 is expected to be a better candidate for oral anti‐AIDS therapies.
Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulations of diltiazem in healthy volunteers
Authors: Guimont Sonia , Landriault Hélène , Klischer Keith , Grace Michael , Lambert Chantal , Caillé Gilles , Gossard Denis , Russell Anthony , Raymond Manon , Hutchings Edna , Spénard Jean
Published: October 2006

Cardizem®SR and Bi‐Tildiem® were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross‐over randomized study, we assessed whether these two sustained‐release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty‐four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high‐performance liquid chromatographic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash‐out. Pharmacokinetics showed statistically significant (p <0.01) differences in AUC0–12 with means (±SD) of 519.2(±172.8) and 429.6(±147.2)ng h ml−1, AUC0–36 of 835.6(±281.6) and 730.9 (±271.5)ng h ml−1 and Cmax of 89.1(±30.3) and 61.1(±21.2) ng ml−1 for Cardizem®SR and Bi‐Tildiem®, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (±SD) change in AUC0–12 of −13.6(±20.8) and +8.4(±31.7) mm Hg h (p = 0.0135) and in AUC0–24 of −33.0(±43.7) and −0.3(±59.2) mm Hg h (p = 0.0463) for Cardizem®SR and Bi‐Tildiem®, respectively. These findings suggest that assessment of efficacy of sustainedrelease formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.
The effect of food on the relative bioavailability of fadrozole hydrochloride
Authors: Choi R. Leslie , Sun Jim X. , Kochak Gregory M.
Published: October 2006

The effect of food on the pharmacokinetic disposition of fadrozole hydrochloride was evaluated in nine healthy male and female volunteers. Single 12 mg doses of fadrozole were orally administered to subjects immediately following a standardized meal or after fasting for 12 h, in a randomized crossover design. No statistically significant treatment differences were detected for the pharmacokinetic parameters AUC and half‐life. Cmax was significantly reduced by 15% for the fed treatment relative to the fasted treatment, and tmax was delayed by 39%. These findings indicate that the concomitant ingestion of food with fadrozole delays the gastric emptying and/or absorption of fadrozole, but has no effect on the extent of absorption.
The effect of chloroquine on the pharmacokinetics and metabolism of praziquantel in rats and in humans
Authors: Masimirembwa C. M. , Naik Y. S. , Hasler J. A.
Published: October 2006

It is likely that a proportion of people treated with the anti‐schistosomicidal drug praziquantel (PZQ) is also taking other drugs such as chloroquine (CHQ), a widely used anti‐malarial. The effect of CHQ on the pharmacokinetics and metabolism of PZQ in rats and in humans was therefore studied. CHQ decreased the bioavailability of PZQ and reduced its maximum serum concentrations to a significant extent in rats and in humans. The clearance was increased to a statistically significant extent in rats but not in humans because of the wide interindividual variation. The effect of CHQ on PZQ pharmacokinetics was unexpected since drugs that inhibit hepatic drug metabolism usually increase the bioavailability of PZQ. We found that CHQ inhibits non‐competitively the metabolism of PZQ to its major metabolite, 4‐hydroxy‐praziquantel, with a Ki of 1.65 mM in rat hepatic microsomes. Maximum concentrations attained by CHQ in serum, however, are low compared to the Ki value and significant inhibition is therefore unlikely in vivo. The explanation for CHQ's effect on the pharmacokinetics of PZQ may be due to other effects of CHQ rather than to a direct effect on drug‐metabolizing enzymes.
The pharmacokinetics and metabolism of DuP 532, a non‐peptide angiotensin II receptor antagonist, in rats and dogs
Authors: Wong Y. N. , Holm K. A. , Burcham D. L. , Huang S.‐M. , Quon C. Y.
Published: October 2006

DuP 532, 2‐propyl‐4‐pentafluoroethyl‐1‐{[2′‐(1H‐tetrazol‐5‐yl)biphenyl‐4‐yl] methyl} imidazole‐5‐carboxylic acid, is an orally active, non‐peptide angiotensin II (AII) receptor antagonist. DuP 532 is more potent and longer acting than losartan, another AII receptor antagonist currently undergoing phase III clinical trials. The pharmacokinetics and the effect of the salt form on the bioavailability of DuP 532 were determined in rats and dogs. In rats, the absolute oral bioavailability and half‐life averaged 8·0% and 3·5 h, respectively, after the sodium bicarbonate solution and 7·6% and 3·6 h, respectively, after the methyl cellulose suspension. In dogs, the absolute oral bioavailability averaged 13.4% after the sodium bicarbonate solution and 11·9% after hard gelatin capsules containing the neat powder. The data demonstrated that there were no differences in bioavailability between the free acid and the sodium salt of DuP 532 after oral administration to rats and dogs.

The in vitro metabolism of 14C‐DuP 532 was evaluated with rat, dog, and human liver microsomes. HPLC analyses with UV and radiochemical flow detection showed that recovery of DuP 532 was greater than 99%, suggesting that there was little if any metabolism by liver microsomal enzymes. Therefore, the low oral bioavailability in rats was probably due to poor absorption of DuP 532 from the GI tract rather than extensive metabolism.
Comparative in vitro and in vivo bioavailability of naproxen from tablet and caplet formulations
Authors: Charles B. G. , Mogg G. A. G.
Published: October 2006

A 500 mg dose of naproxen in a caplet formulation (product A) or a tablet (Naprosyn 500, product B) was administered to 14 fasting healthy subjects on two separate occasions, separated by a 1–2 week washout period in an open, randomized crossover. Blood samples were drawn periodically and plasma naproxen concentrations measured by HPLC. The median time Tmax to reach peak concentration for product A was shorter than that for product B (1·025 h versus 1·5 h) but A and B were similar with respect to median peak plasma concentration Cmax (77·9 mg 1−1 versus 71·4 mg 1−1), and average area AUC0–∞ under the plasma concentration—time curve (1210·2 mg 1−1 h versus 1211·0 mg 1−1 h). In vitro parameters (A versus B) of mean dissolution time MDT (5·03 min versus 15·0 min), and time for 70% dissolution T70 (6·67 min versus 20·2 min), differed significantly.
Glucocorticoid‐dextran conjugates as potential prodrugs for colonspecific delivery: Steady‐state pharmacokinetics in the rat
Authors: McLeod Andrew D. , Tolentino Lorna , Tozer Thomas N.
Published: October 2006

Chronic colitis, e.g., ulcerative colitis and Crohn's disease, is presently treated with glucocorticoids and other antiinflammatory agents. Side‐effects limit chronic glucocorticoid therapy. The dose, and consequently the side‐effects, may be reduced by using prodrugs that selectively deliver drug to the colon. We previously synthesized glucocorticoid‐dextran conjugates in which dexamethasone was attached to dextran (weight‐average molecular weight = 72 600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, dexamethasone‐succinate‐dextran and dexamethasone‐glutarate‐dextran were administered to two groups of male Sprague‐Dawley rats by intragastric infusion. In two additional groups, disodium dexamethasone phosphate and dexamethasone hemisuccinate were each administered by subcutaneous infusion. In a fifth group, dexamethasone was administered by intragastric infusion. All groups were infused for sufficient time for steady state to be achieved. Colon‐specific delivery was quantified using a drug‐delivery index (DDI) in which steady‐state dexamethasone concentrations in the cecum and colon were compared with those measured in blood after separate administrations of dexamethasone and dexamethasone‐dextran conjugate. The colonic DDI values for dexamethasone‐succinate‐dextran and dexamethasone‐glutarate‐dextran were approximately seven and four, respectively. These values were a result of higher tissue concentrations and lower blood concentrations of dexamethasone after intragastric administration of the conjugates compared to subcutaneous and intragastric administration of dexamethasone. The pharmacokinetics of methyl‐prednisolone was also investigated after subcutaneous infusion. Observed cecal and colonic tissue‐to‐blood ratios of 19:1 and 12:1, respectively, showed that this drug is extensively delivered to the large intestine even after subcutaneous administration.
The lack of effect of smoking on the pharmacokinetics and pharmacodynamics of adinazolam and N‐demethyladinazolam
Authors: Chambers J. H. , Fleishaker J. C.
Published: October 2006

The pharmacokinetics and pharmacodynamics of adinazolam and N‐demethyladinazolam (NDMAD) were evaluated in twelve healthy non‐smokers (NS) and twelve smokers (S, ⩾ 20 cigarettes/day) following a single 60 mg dose of adinazolam mesylate sustained‐release tablets in an open‐label, parallel‐group design. Venous blood samples were collected for up to 36 h following drug administration and assayed for adinazolam and NDMAD by HPLC. Urine samples were also collected and assayed for NDMAD by HPLC. Psychomotor performance was measured using the Neurobehavioral Evaluation System. No significant differences were observed in adinazolam oral clearance (51.8±25.8 versus 48.2±14.01 h−1) or peak adinazolam plasma concentrations (Cmax) (93.3±31.8 versus 90.4±18.0 ng ml−1) between groups. NDMAD AUC (2541.457 versus 2798±447 ng h ml−1) and Cmax (173±30.3 versus 175±26.9 ng ml−1) did not differ significantly between groups. NDMAD renal clearance was significantly lower in smokers than non‐smokers (8.7±0.7 versus 10.7±2.71 h−1; p<0.05), but the clinical significance of this observation is unclear. Marginally significant differences were seen between groups in the symbol‐digit substitution and digit span (forward) tasks. The results suggest that smoking has little effect on adinazolam and NDMAD pharmacokinetics or psychomotor effects but that smoking may slightly decrease renal clearance of NDMAD.
An algorithm and computer program for calculating the mean transit time and distribution rate parameters of generated metabolites undergoing linear tissue distribution and linear or non‐linear central elimination
Authors: Cheng Haiyung , Yu Chi , Jusko William J.
Published: October 2006

A method is described for calculating the mean transit time and distribution rate parameters of a generated primary metabolite undergoing linear distribution and linear or non‐linear central elimination, and of catenary metabolites with any precursor order. It is also applicable to a drug and its interconversion metabolite and does not require separate administration of the metabolite. The method allows steady‐state volume of distribution and distribution clearance of a metabolite to be calculated, provided that the central volume of distribution of the metabolite is known. An algorithm and computer program to implement the proposed method are presented. The calculations require the plasma concentration versus time curves of the metabolite and its precursor. The method is applied to both published and simulated data.
Pharmacokinetics of a novel retinoid AGN 190168 and its metabolite AGN 190299 after intravenous administration of AGN 190168 to rats
Authors: Hsyu Poe‐Hirr , Bowen Beta , Tang‐Liu Diane
Published: October 2006

The pharmacokinetics of AGN 190168, a novel synthetic retinoid, and its major metabolite, AGN 190299, in rat blood after intravenous administration was investigated. Approximately 4.4 mg kg−1 (high dose) or 0.49 mg kg−1 (low dose) of AGN 190168 was administered to rats via the femoral vein. Blood was collected from the femoral artery at various time points during an 8 h period. Blood concentrations of AGN 190168 and AGN 190299 were determined by a specific and sensitive high‐pressure liquid chromatographic (HPLC) method.

AGN 190168 was rapidly metabolized in rats. The only detectable drug‐related species in the blood was AGN 190299. Therefore, only pharmacokinetics of AGN 190299 were calculated. Elimination of AGN 190299 appeared to be non‐linear after administration of the high dose, and linear after administration of the low dose. The maximum elimination rate (Vmax) and the concentration at half of the Vmax (km), as estimated by a Michaelis—Menten one‐compartment model, were 7.58 ± 2.42 μg min−1 (mean ± SD) and 6.10 ± 1.58 μg mL−1, respectively. The value of the area under the blood concentration time curve (AUC) was 9.54 ± 1.68 μg h mL−1 after administration of the high dose and 0.594 ± 0.095 μg h mL−1 after administration of the low dose. The clearance value was 7.79 ± 1.20 mL min−1 kg−1 after the high dose, statistically significantly different from that after the low dose (p < 0.05), 14.0 ± 2.2 mL min−1 kg−1. The terminal half‐life (t1/2) was 1.25 ± 0.74 h for the high‐dose group and 0.95 ± 0.16 h for the low‐dose group.

Study results demonstrate rapid systemic metabolism of AGN 190168 to AGN 190299, non‐linear pharmacokinetics of AGN 190299 after the 4.4 mg kg−1 dose, and the lack of difference in disposition profiles between sexes after intravenous administration of AGN 190168 to rats.
Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel
Authors: Sioufi A. , Pommier F. , Boschet F. , Godbillon J. , Lavoignat D. , Salliere D.
Published: October 2006

The percutaneous absorption of diclofenac was studied in ten healthy volunteers treated with Emulgel containing 1.16% diclofenac diethylammonium for 8 d as follows: a single application of 5 g Emulgel on days 1 and 8, and two applications d−1 on days 2–7. Plasma concentration profiles of unchanged diclofenac and urinary concentrations of total diclofenac and metabolites (sum of free and conjugated) were determined.

High inter‐individual variations in plasma and urine data were recorded, due probably to the permeability and the hydration of the skin. Steady state was reached after 2 d of twice‐daily administration. Plasma concentrations were low but remained in the range 10–50 nmol L−1 over the full day for most of the subjects, indicating prolonged absorption from the application site.
Relative bioavailability of four controlled‐release nifedipine products
Authors: Schall R. , Müller F. O. , Hundt H. K. L. , Duursema L. , Groenewoud G. , Van Dyk M. , Van Schalkwyk A. M. C.
Published: October 2006

Four controlled‐release nifedipine products were investigated in two clinical studies. In study 1, 22 healthy male volunteers took part in an open, multiple‐dose, randomized, crossover study to determine the relative bioavailablity of two 10 mg controlled‐release nifedipine tablet (Adalat® Retard, Bayer), administered 12 hourly, and one 20 mg controlled‐release nifedipine tablet (Adalat® Retard, Bayer) administered 12 hourly. In study 2, 24 healthy male volunteers took part in an open, multiple‐dose, randomized, three‐period, crossover study to determine the relative bioavailability of (i) two 30 mg nifedipine gastro‐intestinal therapeutic system (GITS) tablets (Adalat® XL, Bayer) administered once daily; (ii) one 60 mg nifedipine GITS tablet (Adalat® XL, Bayer) administered once daily; and (iii) one 20 mg plus one 10 mg nifedipine controlled‐release tablet (Adalat® Retard, Bayer), administered 12 hourly. In both studies detailed pharmacokinetic data, in particular with respect to the controlled‐release characteristics of the different formulations, were collected.

Results of both studies indicate that all nifedipine products investigated are bioequivalent with respect to the extent of absorption of nifedipine. The nifedipine GITS products (Adalat® XL) have better controlled‐release properties than the Adalat® Retard product, and are suitable for once‐a‐day administration.
The influence of food on the disposition of the antiepileptic oxcarbazepine and its major metabolites in healthy volunteers
Authors: Degen P. H. , Flesch G. , Cardot J.‐M. , Czendlik C. , Dieterle W.
Published: October 2006

The effect of food on the pharmacokinetics of the antiepileptic oxcarbazepine (OXC) was investigated in healthy volunteers. Six healthy male volunteers were treated with single peroral doses of 600 mg of oxcarbazepine (Trileptal®) after overnight fasting or a fat‐ and protein‐rich breakfast. Mean (± SD) areas under the plasma concentration—time curves (AUC) of the major component in plasma, the active monohydroxy metabolite (MHD), which is responsible for the therapeutic effect in man, were 672 (25) μmol L−1 h when given to the fasted volunteers and 780 (31) μmol L−1 h (p = 0.042) when given after a substantial breakfast. Mean (± SD) maximum concentrations (Cmax) were 25.5 (4.8) μmol L−1 when given to the fasted volunteers and 31.4 (5.3) μmol L−1 (p = 0.025) when given after breakfast. Thus, the average AUC was increased by 16% and Cmax by 23% when oxcarbazepine was given with food. The times at which Cmax was reached (tmax) as well as the terminal half‐lives were not influenced by concomitant intake of food. The tolerability was the same whether oxcarbazepine was given before or after food in healthy volunteers. The slight effect of food on the kinetics of oxcarbazepine should be of little therapeutic consequence.
Griseofulvin absorption from different sites in the human small intestine
Authors: Gramatté T.
Published: October 2006

The site‐dependent small‐intestinal absorption pattern of griseofulvin was investigated in man. Griseofulvin was chosen as a model substance having extremely low water solubility and moderate lipid solubility. A conventional steady‐state perfusion technique (triple‐lumen tubing system with a 20 cm test segment) was applied. Dissolved griseofulvin (10.0 mg L−1) was perfused (10 mL min−1) during 160 min into different parts of the small intestine with the middle of the test segment between 85 cm and 270 cm beyond the teeth. Each of the ten healthy volunteers was examined twice with the test segment localized in different regions to allow for intraindividual comparisons. Mean drug absorption rates calculated from intestinal aspirate concentrations were similar in the two intestinal parts (proximal, 15.0 ± 5.9 μg (20cm min)−1; distal, 16.2 ± 4.3 μg (20 cm min)−1; mean ± SD). Absorption rate was strongly correlated to the amount of griseofulvin offered to the test segment per unit time. Extrapolating these findings it follows that an amount of griseofulvin, once dissolved, would be absorbed completely (>99%) along 100 cm of the small intestine. A significant, positive correlation between the rate of transmucosal fluid transport and the absorption rate of griseofulvin was observed in the distal parts investigated.
The effect of the fat content of food on the pharmacokinetics and pharmacodynamics of SDZ FOX 988, an antidiabetic agent, in the dog
Authors: Lau David T.‐W. , Kalafsky G. , Aun Renee L. , Tse Francis L. S.
Published: October 2006

SDZ FOX 988 (FOX 988) is being developed for the treatment of type II diabetes. The objective of this study was to examine the effect of the fat content of food on the pharmacokinetics and pharmacodynamics of FOX 988 following oral administration in the dog. In a randomized, cross‐over design, four dogs received a single 10 mg kg−1 dose of 14C‐FOX 988 suspension concomitantly with food containing 10% fat or 40% fat, or with the 10% fat food at 4 h post‐dose. Serial blood, urine, and fecal samples were collected for 96 h and analyzed for total radioactivity. Blod concentrations of 53–450, the active metabolite of FOX 988, were also determined. Serum concentrations of β‐hydroxybutyrate and glucose, pharmacological markers for the antidiabetic effects, were measured serially for 24 h after dosing. The animals receiving the low‐fat meal at dosing and at 4 h post‐dose exhibited similar extents of absorption, as shown by similar AUC values and urianry radioactivity recovery. Administration of the high‐fat meal at dosing significantly enhanced the absorption of FOX 988 and resulted in high blood concentrations of 53–450. However, no significant differences in the pharmacological activity of the drug were observed among the three treatments.
Uptake and biodisposition of 2‐ylcyanamide‐1,3,4‐thiadiazole (LY217896) by red blood cells
Authors: Bonate Peter L , Peyton Albert
Published: October 2006

In man, 14C‐2‐ylcyanamide‐134‐thiadiazole (LY217896) accumulates into red blood cells (RBCs) where it is rapidly metabolized. Both in man and ex vivo, within a few hours of administration of 14C‐LY217896 at least two intracellular metabolites were detected within the RBCs using HPLC. These metabolites were never detected extracellularly. After 24 h no detectable radioactivity was found in the plasma and all the radioactivity was detected within the cellular fraction. All radioactivity was identified as a single peak within the RBCs, indicating the metabolite(s) to be highly polar compared to LY217896. Parent LY217896 was never detected within the RBCs at any time point, suggesting transport, either by diffusion or a carrier mediated mechanism, was the rate limiting step. Due to the nature of the preparation it was impossible to separately characterize uptake and biotransformation. Nevertheless, uptake/biotransformation was found to be temperature sensitive, sodium independent, and energy dependent. Both niacin and vitamin B6, but not nicotinamide, competitively blocked the uptake and subsequent intracellular metabolism of LY217896.
Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals
Authors: Kararli Tugrul T.
Published: October 2006

In addition to metabolic differences, the anatomical, physiological, and biochemical differences in the gastrointestinal (G.I.) tract of the human and common laboratory animals can cause significant variation in drug absorption from the oral route. Among the physiological factors, pH, bile, pancreatic juice, and mucus and fluid volume and content can modify dissolution rates, solubility, transit times, and membrane transport of drug molecules. The microbial content of the G.I. tract can significantly affect the reductive metabolism and enterohepatic circulation of drugs and colonic delivery of formulations. The transit time of dosage forms can be significantly different between species due to different dimensions and propulsive activities of the G.I. tract. The lipid/protein composition of the enterocyte membrane along the G.I. tract can alter binding and passive, active, and carrier‐mediated transport of drugs. The location and number of Peyer's patches can also be important in the absorption of large molecules and particulate matter.

While small animals, rats, mice, guinea pigs, and rabbits, are most suitable for determining the mechanism of drug absorption and bioavailability values from powder or solution formulations, larger animals, dogs, pigs, and monkeys, are used to assess absorption from formulations. The understanding of physiological, anatomical, and biochemical differences between the G.I. tracts of different animal species can lead to the selection of the correct animal model to mimic the bioavailability of compounds in the human.

This article reviews the anatomical, physiological, and biochemical differences between the G.I. tracts of humans and commonly used laboratory animals.
The acetylcholinesterase oxime reactivator HI‐6 in man: Pharmacokinetics and tolerability in combination with atropine
Authors: Clement John G. , Bailey David G. , Madill Herbert D. , Tran Lan T. , Spence J. David
Published: October 2006

In a double‐blind, placebo‐controlled, single‐dose ascending pharmacokinetics and tolerance study, we evaluated the bispyridinium oxime HI‐6 dichloride monohydrate (62.5, 125, 250, and 500 mg), administered intramuscularly with atropine sulphate, 2 mg, in 24 healthy male volunteers. The plasma HI‐6 peak concentration (Cmax) and area under the concentration—time curve (AUC) demonstrated linear pharmacokinetics with low intradose variability, suggestive of uniformity of effect among subjects. HI‐6 (500 mg) attained plasma drug concentrations that appeared adequate for practical use as an antidote. The mean ± SD time to maximum plasma HI‐6 concentration (tmax = 0.69 ± 0.21 h, n = 16), and absorption half‐life (t/2a = 0.17 ± 0.05 h) indicated rapid onset of effect. The volume of distribution (Vd = 0.25 ± 0.04 L kg−1 TBW) approximated the extracellular fluid volume. A high total body clearance (CL = 252 ± 52 mL min−1) and short apparent elimination half‐life (t/2e = 1.15 ± 0.19 h) were expected for this polar quaternary ammonium drug. The renal clearance (CLr = 137 ± 33 mL min−1), which approximated the expected glomerular filtration rate, and 24 h urinary excretion of unchanged drug (55 ± 10%) indicated substantial non‐renal elimination. Blood pressure, heart rate, respiratory rate, electrocardiographic parameters, mental acuity, and vision were not altered. Adverse events and changes in serum, urine and semen laboratory tests were mild. The pharmacokinetics, safety, and apparent efficacy of HI‐6 suggest it may be a superior oxime antidote against nerve agent poisoning.
Pharmacokinetics and antitumour activity of a new anthracycline, DA‐125, after intravenous administration to subcutaneously implanted Lewis‐lung‐carcinoma‐bearing mice
Authors: Lee Sang D. , Park Jeong B. , Lee Woo I. , Shim Hyun J. , Lee Eung D. , Lee Jong J. , Kim Won B. , Yang Junnick , Kim Chong K. , Lee Myung G.
Published: October 2006

The pharmacokinetics and tissue distribution of M1–M4 were compared after intravenous (IV) administration of DA‐125, 25 mg kg−1, to BDF1 mice (n = 5 at each sampling time) and subcutaneously implanted Lewis‐lung‐carcinoma‐bearing BDF1 mice (n = 10 at each sampling time). The mean plasma concentrations of M1–M4 were not significantly different between the two groups of mice, and hence similar pharmacokinetic parameters for M1–M4 were obtained. The amount of M1 in the lung was significantly greater in the tumour‐bearing mice than in the control mice, resulting in a greater AUA, in the tumour‐bearing mice (18 600 against 8940 μg min g−1), and vice versa in the liver (962 against 3840 μg min g−1). However, the corresponding values for other tissues were comparable between the control and tumour‐bearing mice. The amount of M1 was greatest in the lung for up to 2 h in the tumour‐bearing mice. M2 was the predominant metabolite among M1–M4 excreted in 24 h urine by both groups of mice; 8.36 and 10.7% of the IV dose were excreted in 24 h urine as M2–expressed in terms of DA‐125—by the control and tumour‐bearing mice, respectively. The amount of M1 in the tumour mass reached a mean Cmax of 3.75 μg g−1 immediately after IV administration of DA‐125 to the tumour‐bearing mice, then declined very slowly to an amount that remained almost constant for up to 24 h. This suggested that M1 has high affinity for the subcutaneously implanted Lewis lung carcinoma. The antitumour activity, such as the increase in life span (ILS) and tumour growth inhibition (TGI) of DA‐125, 6–48 mg kg−1, and adriamycin (ADM), 3–18 mg kg−1, were also compared in subcutaneously implanted Lewis‐lung‐carcinoma‐bearing BDF1 mice after four weekly IV administrations of the drugs on days 1, 8, 15, and 22 following tumour implantation. More than three out of six mice survived as tumour‐free for longer than 70 d at a DA‐125 dose range of 6–24 mg kg−1, but there were no tumour‐free mice at any dose of ADM. Assuming ILS values higher than 30% to be effective, DA‐125 doses ranging from 6 to 24 mg kg−1 were effective in increasing the life span, which ADM dose only within the dose range of 6–12 mg kg−1.
Pharmcokinetics of HI‐6 and atropine in anaesthetized pigs after administration by a new autoinjector
Authors: Nyberg Ann Göransson , Cassel Gudrun , Jeneskog Torgny , Karlsson Lena , Larsson Roland , Lundström Marlene , Palmer Lena , Persson Sven‐Åke
Published: October 2006

A newly developed autoinjector (Astra Tech, Sweden) containing 500 mg HI‐6 and 2 mg atropine sulphate was tested in anaesthetized normal pigs. The pharmacokinetics and pharmacodynamics of the drugs after administration by the autoinjector were compared with those after conventional needle and syringe delivery intramuscularly and intravenously. Cardiopulmonary parameters were monitored and serum concentrations of oxime, atropine, and acetylcholinesterase were determined in blood samples taken at intervals over a 6h period postinjection. After injection in anaesthetized pigs, both HI‐6 and atropine were absorbed rapidly and completely from the injection site. Therapeutic serum concentrations of HI‐6, arbitrarily taken as 4 μg mL−1, were reached within 1 min of intravenous and autoinjector administration, and within 5 min of intramuscular injection. The concentrations remained above this level for 3–4h. There were no significant changes in acetylcholinesterase activity, mean arterial blood pressure, or respiration frequency after injection of HI‐6 and atropine sulphate. The heart rates increased significantly after administration of the two drugs (cardioacceleration defined as ⩾ 5% increase in heart rate), regardless of the technique employed. Our results show that HI‐6 and atropine sulphate can be given intramuscularly by the new autoinjector with the same effectiveness and speed as when given intravenously. Irrespective of the injection technique, no overt signs of toxicity were observed at the drug concentrations used.