bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioequivalence of two pharmaceutical forms of diltiazem
Authors: Rubio Modesto , Masana Mónica I. , Garcilazo Enrique , de Los Santos Antonio R. , di Girolamo Guillermo
Published: October 2006

Diltiazem, a calcium‐channel blocking agent, has been shown to be a potent coronary vasodilator used in the treatment of ischaemic heart disease. The present study was conducted to compare the bioavailability of regular 60 mg tablets administered every 6 h with sustained release capsules of 120 mg administered every 12 h. High‐performance liquid chromatographic analysis was carried out for determination of diltiazem and one of its metabolites desacetildiltiazem in six male patients. The relative bioavailability of this sustained‐release pharmaceutical form did not show any significant difference with that of tablets.
The disposition of cytosine arabinoside and its metabolite after single doses to rabbits
Authors: Zimmerman Cheryl L.
Published: October 2006

Cytosine arabinoside (ara‐C) is rapidly deaminated vivo to ara‐U by cytidine‐deoxycytidine deaminase. The purpose of this study was to determine the contribution of the deamination pathway to the overall clearance of ara‐C after a single dose to rabbits, as well as to determine the pharmacokinetics of ara‐U itself. Male rabbits were cannulated in the marginal ear vein and received a single IV bolus dose (50 mg kg −1) of either ara‐C (n=10) or ara‐U (n=10). Blood samples were collected for up to 24 h. One week later, the rabbits received the opposite treatment. Plasma samples were analyzed by reversed‐phase HPLC. The plasma clearance of ara‐C (8·16 ± 2·43 ml min−1 kg−1) was significantly higher than the clearance of ara‐U (5·66 ± 2·59 ml min−1 kg−1). The volume of distribution of ara‐C was 0·64 ± 0·161 kg−1 (mean ± SD) and was significantly smaller (p <0.05) than that of ara‐U (1·22 ± 0·701 kg−1). As a result, the elimination rate constant of ara‐C was significantly larger than that of ara‐U (0·602 ± 0·097 h−1 vs 0·258 ± 0·051 h−1). In the rabbits that received both treatments (n=7), the fraction of the ara‐C dose metabolized to ara‐U (fm) was 0·53 ± 0·20. Qualitatively, the pharmacokinetics of ara‐C and ara‐U resemble those in humans. This study provides the basis for further work into the modulation of ara‐C disposition either by ara‐U or other agents.
Influence of lovastatin on the pharmacokinetics, toxicity and immunologic response of cyclosporine in the obese zucker rat
Authors: Berens Kurt L. , Vadiei Kiumars , Brunner Lane J. , Wasan Kishor M. , Luke David R.
Published: October 2006

The combined use of lovastatin, a hypolipidemic agent effective in the reduction of cholesterol levels, and the lipophilic immunosuppressant, cyclosporine, was studied in the obese rat model. Pharmacokinetics, immunosuppressive activity, lipid levels, and creatinine clearances were compared between groups administered drug‐free vehicle, lovastatin or cyclosporine alone, or concomitant cyclosporine and lovastatin. All groups were pre‐treated with either oral lovastatin 2.5 mg kg−1 day−1 or propylene glycol vehicle for 1 week. Although no differences in renal function were observed in rat groups administered cyclosporine or lovastatin alone, there was a significant reduction in baseline creatinine clearance following combination therapy compared to placebo controls (70 ± 18 vs 121 ± 16 per cent of baseline; p<0·05). No differences in trough cyclosporine concentrations were observed between groups. Similarly, mean areas under the whole blood concentration‐time profiles were not significantly different with or without concomitant lovastatin (61823 ± 27295 vs 41470 ± 10312 ng h ml−1;p=0·13). No differences in systemic clearance or volume of distribution of parent cyclosporine were observed with combination therapy. Furthermore, lipid levels and T‐lymphocyte activity were unchanged with the addition of lovastatin. Per cent increases in creatine kinase were significantly correlated with percentage drop in baseline renal function, suggesting the development of rhabdomyolysis. The present data support the interaction between cyclosporine and lovastatin observed clinically, resulting in acute renal dysfunction. Caution should be exercised in their combined use.
Oxcarbazepine disposition: Preliminary observations in patients
Authors: Kumps A. , Wurth C.
Published: October 2006

We describe a preliminary retrospective study based on the concentration of two hydroxylated metabolites of oxcarbazepine (OCZ), a new anticonvulsant substance, measured in the plasma of 15 patients with epilepsy. Their ages ranged from 8 to 68 years. 6 of them also received phenobarbital and/or phenytoin as co‐medication. The concentration of 10‐hydroxy‐10,11‐dihydrocarbamazepine (HCBZ) or of trans‐10,11‐dihydroxy‐10,11‐dihydrocarbamazepine (DHCBZ), the metabolites measured, are significantly correlated with the dose of OCZ (p < 0·05 and p < 0·01, respectively). DHCBZ concentrations, standardized to a constant OCZ dose or to a constant HCBZ concentration, are significantly higher during co‐medication (p < 0·01 and p < 0·05, respectively); HCBZ levels are unaffected. These results confirm that enzyme‐inducing drugs, although accelerating the oxidation HCBZ, do not induce its formation. Since HCBZ is the active metabolite, such drug interaction seems unlikely to alter OCZ pharmacological activity.
Elevation of carbamazepine plasma levels by diltiazem in rabbits: A potentially important drug interaction
Authors: Al‐Humayyd Mohammad Saad
Published: October 2006

The effect of diltiazem on the plasma level of carbamazepine (CBZ) was investigated in rabbits. The animals were given either CBZ alone or in combination with diltiazem and plasma samples were collected at different time intervals. The concentration of CBZ was detected using an HPLC method. Diltiazem significantly increased the area under the curve (AUC), the maximum plasma concentration (Cmax), and the elimination half‐life (t1/2) of CBZ (p < 0·05). These results suggest that a potentially harmful drug‐ drug interaction may occur if CBZ and diltiazem are administered concurrently.
Pharmacokinetics of morphine and its surrogates XI: Effect of simultaneously administered naltrexone and morphine on the pharmacokinetics and pharmacodynamics of each in the dog
Authors: Langguth Peter , Khan Patricia J. , Garrett Edward R.
Published: October 2006

There were no dramatic modifications of the pharmacokinetics in the dog of i.v. bolus doses of 0·5, 2·7 and 5 mg kg−1 morphine by coadministering i.v. 5 mg kg−1 naltrexone as bolus injections over 15–20s and 12·3 mg kg−1 by continuous infusion. Morphine's terminal half‐life, clearances, apparent volumes of distribution (except for that of the central compartment), percentages of drug and conjugated metabolite excreted in urine and bile did not differ significantly by paired t‐test (probability (p) > 0·5 for rejection of the null hypothesis of no difference) when naltrexone was coadministered. There were no statistically significant (by t‐test) modifications of the plasma pharmacokinetics in the dog of i.v. bolus doses of 5 mg kg−1 naltrexone with and without morphine coadministration except for the coefficient of the second (or terminal) exponential of the sum that fitted the plasma concentration‐time data of naltrexone. Although morphine coadministration did not significantly affect the terminal half‐life of naltrexone, its clearances or apparent volumes of distribution by t‐test of the differences between averages (with each dog equally weighted), drug coadministration did significantly (by t‐test) affect the fraction of naltrexone dose secreted into bile as conjugate (fB), the fraction of the dose excreted as conjugate in urine, and the fraction excreted elsewhere (fB). Although naltrexone reversed the central action of morphine in affecting monitored pupil diameters, it did not antagonize the peripheral effects of morphine in perturbing renal and biliary flow rates. This led to a larger fraction of the naltrxone does being metabolized to conjugate on morphine coadministration. Since less naltrexone conjugate was renally and biliary excreted initially, due to morphine inhibition of the initial renal and biliary processes, naltrexone conjugate plasma concentrations were higher when morphine was coadministered.
Modfit: A pharmacokinetics computer program
Authors: Allen Graham D.
Published: October 2006

This paper presents a computer program, MODFIT, written in FORTRAN, primarily for use on the Digital Equipment Company VAX series computers for the mathematical analysis of concentration‐time data. Drug data generated from biological fluids and tissues may be fitted by a variety of different models. For many models, parameter starting estimates are program generated prior to automatic nonlinear regression analysis using a modified Davidon‐Fletcher‐Powell algorithm. The output of results is extensive and plotting facilities are available. Explicit and differential equation models may be fitted to single dose data and simulations using all models (single or repeat dose) may be employed to generate drug concentration‐time data with plotting output. The package has been tested on numerous data with no problems regarding local function minima. Some comparisons with existing programs have been made and MODFIT compares well with respect to robustness, efficiency, and ease of use.
Assay of glyceryl trinitrate, isosorbide dinitrate, and their metabolites in plasma by large‐bore capillary column gas‐liquid chromatography
Authors: Booth Brian P. , Bennett Brian M. , Brien James F. , Elliott Douglas A. , Marks Gerald S. , McCans John L. , Nakatsu Kanji
Published: October 2006

Two large‐bore capillary columns, one with dimethyl polysiloxane (HP‐1®) as the stationary phase and the other with phenyl (50 per cent) methyl (50 per cent) polysiloxane (DB‐17), were used to develop gas‐liquid chromatographic (GLC) assays for measuring isosorbide dinitrate (ISDN), glyceryl trinitrate (GTN), and their metabolites. ISDN, isosorbide‐2‐mononitrate (2‐ISMN), and isosorbide‐5‐mononitrate (5‐ISMN) in plasma, ranging in concentration from 1 to 300 nM, and GTN, glyceryl‐1,2‐dinitrate (1,2‐GDN). and glyceryl‐1,3‐dinitrate (1,3‐GDN), ranging in concentration from 3 to 60 nM in plasma, were analysed on both columns. GLC analysis yielded baseline resolution of the analytes. The method using the dimethyl polysiloxane column gave a lower limit of detectability for GTN of 0·75 nM (signal/noise (s/n) = 2), and the procedure using the phenyl‐methyl column provided a lower limit of detectability for ISDN of 81 pM (s/n = 2). The large‐bore column GLC procedures exhibited shorter retention times for both ISDN and GTN than those previously reported for capillary‐column assays. The chromatographic resolution of analytes and column efficiency of the large‐bore capillary columns were comparable to the results previously found using capillary‐column GC. The assays for ISDN and GTN have been shown to be appropriate for pharmacokinetic studies in volunteers and patients. We determined that the HP‐1® column is appropriate for the analysis of GTN and metabolites, and the DB‐17 column is suitable for analysis of ISDN and its metabolites. We conclude that the use of large‐bore capillary columns provides rapid and reliable GLC assays for organic nitrates.
Placental transfer and tissue distribution of vitamin e in pregnant rabbits
Authors: Bortolotti A. , Traina G. L. , Barzago M. M. , Celardo A. , Bonati M.
Published: October 2006

α‐Tocopherol (vitamin E) is widely prescribed in neonatal intensive care units, in large doses and by different schedules, for the prevention of retrolental fibroplasia, intraventricular haemorrhage, bronchopulmonary dysplasia, and haemolytic anaemia. Since the efficacy of the drug in premature newborns seems related to early administration, the physicochemical characteristics of the drug itself and available formulations limit the major therapeutic aim of promptly raising levels of vitamin E in premature babies during the early hours of life. It has thus been suggested that vitamin E be given to the mother before delivery to produce higher drug concentrations in the newborn.

To see whether this would work, the tissue distribution and transplacental transfer of vitamin E were studied in six pregnant rabbits at steady‐state after an i.v. bolus + infusion to give a mean venous blood concentration of about 325 μmol l−1 of a‐tocopherol acetate, corresponding to about 30 μmol l−1 of α‐tocopherol. Endogenous levels were measured in six control pregnant rabbits.

In treated animals α‐tocopherol was increased in liver, spleen, placenta, lung, mammary gland, blood, and bile but not in brain, heart, fat, muscle or adrenals probably because distribution into these tissues is very slow. Vitamin E levels in the placenta of treated mothers were 15 times those of control rabbits, but the vitamin was not detectable in amniotic fluid and only very low levels were found in fetal blood.

These findings do not indicate any advantage of giving mothers a‐tocopherol acetate before delivery.
Pharmacokinetics of midaglizole, a new hypoglycaemic agent, in healthy subjects
Authors: Nomura Hisashi , Yamada Fusako , Hakusui Hideo
Published: October 2006

The objective of this study was to evaluate the pharmacokinetics of midaglizole, a new orally effective hypoglycaemic agent, in healthy male subjects. In Study I, volunteers were given single oral doses of 150, 200, 300, and 500 mg of midaglizole 20 min before breakfast. In Study II, 200 mg of midaglizole was given 30 min after breakfast. In Study III, multiple oral administration study was carried out at a dose of 200 mg t.i.d. 20 min before meals for 7 days.

The disposition of midaglizole was adequately described by a one‐compartment open model with first order absorption. It was essentially dose‐independent up to 500 mg given orally. The pharmacokinetic parameters calculated by employing this model indicated that the disposition of this drug was characterized by good absorption from the intestine, a wide distribution in the body, and a rapid excretion via the kidneys. The absorption rate of midaglizole from the intestine was definitely slowed by the presence of food, probably due to a decrease in the rate of gastric emptying. No clinical significant accumulation of midaglizole in the body was observed during or after multiple doses.

A linear correlation was found between the area under the curve of plasma concentration of midaglizole versus time and the area calculated from the curve of change in blood glucose level versus time after oral administration of midaglizole.
Moment method for the estimation of mass transfer coefficients for physiological pharmacokinetic models
Authors: Gallo James M. , Lam Fred C. , Perrier Donald G.
Published: October 2006

In vitro and in vivo techniques have been utilized to estimate mass transfer coefficients for physiological pharmacokinetic models. No single method has been adopted for estimating this parameter, in part, due to the different model structures with which this parameter may be associated. A specific method has been derived to calculate mass transfer coefficients for non‐eliminating membrane‐limited tissue compartments. The present method is based on observed concentration–time data, and requires the calculation of the areas under the zero and first moment curves for plasma, and the first moment curve for the tissue. A Monte Carlo simulation technique was used to determine the percentage biases of the method based on a published model for streptozoticin and adriamycin. For the latter model, the method was compared to a non‐linear regression parameter estimation technique.
Efficiency of different criteria for selecting pharmacokinetic multiexponential equations
Authors: Imbimbo Bruno P. , Martinelli Paolo , Rocchetti Maurizio , Ferrari Gianni , Bassotti Gabrio , Imbimbo Ennio
Published: October 2006

Several statistical and empirical approaches have been proposed to select the multiexponential equation that best describes the time course of the plasma concentration of a drug. Recently, a new criterion (Ip) has been proposed according to which the model that best interprets a set of experimental data points is the one with the smallest area between the approximate confidence limits of estimated plasma concentration. We used large Montecarlo simulations to compare the ability of different selection criteria to select the correct model from data generated with an independent, normally distributed random error. The new criterion (Ip), Akaike's information criterion, the Schwartz test, and the F ratio test were studied. In this situation, the correct model was known and the performances of different selecting methods were assessed by examining their sensitivity to the number of exponential terms, the number of data points, and the size of the exponents in the true model. Mono‐, bi‐, and triexponential equations were studied. Overall mean percentages of right identification were 98·1 per cent for the new index, 82.8 per cent for Akaike's information criterion, 89.5 per cent for the Schwartz test, and 97.7 per cent for the F ratio test. The Akaike and Schwartz tests were not as efficient as the other tests with few (8–10) data points. The Ip and the F test raise the percentages of right identification of the model when the hybrid elimination rate macroconstants differ by at least a factor of four. These large simulations show that the new selection criterion for pharmacokinetic multiexponential equations compares well with the F test and is superior to the Akaike and Schwartz tests.
Plasma concentrations of disulfiram after injection of suspended micropellets into alcoholic subjects
Authors: Cid Edison , Cid Edison , Feuerhake Oscar , Boisier Iris , Chandía Rolando
Published: October 2006

The disposition of disulfiram after administration in a new formulation was studied in rats and alcoholic patients. The suspension consisted of microcrystals suspended in a mixture of propylene glycol and water and injected subcutaneously into rats and humans; the course of the plasma concentration of diethyldithiocarbamate with time was followed by gas–liquid chromatography. Systemic delivery of disulfiram was observed to occur for a month. The data demonstrate that this form has the properties of a sustained‐release formulation when implanted subcutaneously. There was no evidence of local or systemic adverse reactions.
HI‐6 and 2‐pam in sheep: Pharmacokinetics and effects on muscle tissue following intramuscular injection
Authors: Moore David H. , Hayward Isaac J. , Steve Tucker F. , Lukey Brian
Published: October 2006

The pharmacokinetics of 2‐PAM, a component of the current nerve agent antidote therapy for U.S. military forces was compared to the pharmacokinetics of another acetylcholinesterase reactivator HI‐6. Additionally, the effects of these compounds on muscle tissue following intramuscular injection was examined. Plasma concentrations of the oximes were determined by HPLC. Plasma concentration—time profiles for both oximes fit a one‐compartment open model with first‐order absorption and elimination. The results demonstrate that the half‐time of absorption of the two oximes are nearly the same while the maximum plasma concentration of HI‐6 was significantly higher than that for 2‐PAM. Musculoirritancy was assessed on the basis of quantitative histological examinations of the injection sites and by the measurement of serum creatinine phosphokinase. Comparison of the scores from the histological sections demonstrate no difference between the two oximes. Serum creatinine phosphokinase values were elevated following injections of HI‐6, but were not consistently elevated following the 2‐PAM injections.
A method for calculating the mean residence times of catenary metabolites
Authors: Cheng Haiyung
Published: October 2006

A method for calculating the mean residence times of metabolites in the body, systemic circulation, and peripheral tissue is described. The calculations require the AUC, AUMC, and derivatives of the plasma concentration versus time curves of the metabolite and its precursor. The method is applicable to metabolites with any precursor order and does not require separate administration of the metabolite. The approach is applied to published data for the primary and secondary metabolites of ketamine.
Pharmacokinetics and oral bioavailability of carbimide in man
Authors: Obach R. , Torrent J. , Colom H. , Pruñonosa J. , Peraire C. , Domenech J.
Published: October 2006

A pharmacokinetic study of carbimide, an inhibitor of aldehyde dehydrogenase, used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in male human volunteers for intravenous and oral administration. Carbimide plasma concentrations were determined by a sensitive and specific high performance liquid chromatographic method. The intravenous doses administered were 0·1, 0·3, 0·6, and 1 mg kg−1 and linear pharmacokinetics were observed for this dose range. Elimination half‐life and total plasma clearance values ranged from 42 to 52 min and from 14·4 to 20·5 ml kg−1 min−1, respectively. After oral administration of 1 and 1·5 mg kg−1 of carbimide, elimination half‐life values were 75 and 61 min, respectively, being higher than the corresponding value obtained after 0·3 mg kg−1 doses, i.e. 39 min. In all cases, rapid absorption was indicated by tmax values ranging from 10·5 to 15·5 min. Absorption was not complete, the oral bioavailability being 53 per cent and 70 per cent for the 0·3 and 1 mg kg−1 carbimide dose, respectively. The data indicate that there is a first‐pass effect for carbimide.
Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects
Authors: Baldock G. A. , Brodie R. R. , Chasseaud L. F. , Taylor T. , Walmsley L. M. , Catanese B.
Published: October 2006

The pharmacokinetics of the anti‐inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min−1) but high volume of distribution (ca. 1101); the apparent terminal half‐life in plasma was ca. 8h. Benzydamine was well absorbed after oral administration, as indicated by a mean systemic availability of 87 per cent. However, absorption of the drug was low (<10 per cent of the dose) after its use by male subjects as a mouthwash, or after its application to female subjects as dermal cream and vaginal douche preparations. The data suggest that benzydamine is generally not well absorbed through the skin and non‐specialized mucosae, thereby limiting unrequired systemic exposure to this drug when it is used by these routes.
The pharmacokinetics of atropine and diazepam in sheep: Intramuscular co‐administration
Authors: Moore David H. , Smallridge Robert C. , Von Bredow Jurgen D. , Lukey Brian J.
Published: October 2006

The purpose of this study was to determine whether the co‐administration of atropine and diazepam affect the rate and extent of absorption of either drug. A triple crossover pharmacokinetic study using adult sheep was conducted. Each of nine animals received single injections of atropine (2mg), diazepam (10mg), and a combination of the two compounds weekly over a 3‐week period. The combination of the drugs was injected into a single intramuscular site through a specially designed tandem syringe. Blood samples were obtained from time 0 to 300 min post‐injection. Serum samples were analyzed for atropine by radioimmunoassay and for diazepam by gas chromatography/mass spectrometry. Pharmacokinetic parameters were evaluated by non‐compartmental analysis. The co‐administration of atropine and diazepam intramuscularly in sheep caused a delay in the time to reach maximal concentration of atropine. However, at the time when a single injection of atropine reached its maximum serum concentration, 92 per cent of that concentration was reached by atropine in the presence of diazepam. Additionally, no difference was detected in the rate or extent of diazepam absorption when administered intramuscularly in combination with atropine at the same site.
Nonlinearities in amoxycillin pharmacokinetics I. Disposition studies in the rat
Authors: Torres‐Molina F. , Peris‐Ribera J. E. , García‐Carbonell M. C. , Aristorena J. C. , Granero L. , Plá‐Delfina J. M.
Published: October 2006

Several features of amoxycillin pharmacokinetics in man are not well known in spite of the extensive clinical use of the antibiotic. In this paper it is demonstrated that amoxycillin disposition kinetics in rats is clearly nonlinear, and that this may be due mainly to its elimination mechanisms. At different intravenous bolus dose levels, and in steady‐state perfusion studies, the most striking feature is an increased renal clearance as dose increases (from 3·5 to 7·0 mg kg−1 for intravenous bolus, and from 4·6 to 20·0 μg min−1 for intravenous perfusions). This phenomenon has been attributed to a saturation of the active renal tubular reabsorption of the antibiotic. When the intravenous dose is substantially increased (28·0 mg kg−1 bolus), plasma clearance tends to stabilize, probably because saturation of the active tubular secretion of amoxycillin takes place at these doses. Extrarenal clearance seems to remain linear throughout the entire dose range. On the basis of these observations and a review of selected bibliography, an interpretation of the kinetic disposition behaviour of amoxycillin in man is attempted.
Nonlinearities in amoxycillin pharmacokinetics II. Absorption studies in the rat
Authors: Torres‐Molina F. , Peris‐Ribera J. E. , García‐Carbonell M. C. , Aristorena J. C. , Plá‐Delfina J. M.
Published: October 2006

Most factors influencing amoxycillin oral absorption are, even today, unknown. Since many dosage schedules have been shown to lead to incomplete absorption, it would be desirable to find a suitable animal model where these factors could be studied in depth. In this paper, it is shown that, in the rat, plasma level curves obtained after oral doses of 7 and 28 mg kg−1 are poorly fitted using first‐order absorption kinetics and that the best fit is obtained through the use of an input equation combining zero and first‐order kinetics. In contrast, plasma level curves found after intraduodenal administration of amoxycillin solutions (7 mg kg−1) are well fitted by first‐order input kinetics. It would seem that precipitation of some dose fraction of the orally administered antibiotic may occur in proximal gastrointestinal areas; this plays an important role in absorption profiles and prevents any possible saturation phenomena associated with active intestinal transport of the antibiotic. A comparative study of available human oral data revealed close similarities with those found in rats. As a result, the plasma level curve fitting was greatly improved by the use of the input function described here for the rat. Although oral bioavailability (as assessed from urinary excretion data) is lower in this latter species, the use of suitable correction factors led to superimposable plasma level curves in the two species, as occurred in previously reported disposition studies.
Pharmacokinetics and acetylation of sulfa‐2‐monomethoxine in humans
Authors: Vree Tom B. , Kolmer Eleonora W. J. Beneken , Hekster Yechiel A. , Shimoda Minoru , Ono Makoto , Miura Tadayoshi
Published: October 2006

In humans sulfa‐2‐monomethoxine (S) is metabolized by N4‐acetylation (39.9 ± 8.0 per cent). After an oral dose, S is eliminated biphasically (t½, 5·2 ± 1·6h and 13·2 ± 3·4h) which is similar in both fast and slow acetylators. The metabolite N4‐acetylsulfa‐2‐monomethoxine (N4) is eliminated monophasically (t½, 30·0 ± 5·7h). The intrinsic mean residence time (MRT) of NM4 is 33·5 ±8·8h. The mean total body clearance of S is 11·6 ±2·7 ml min−1, and the Vdss is 12·3 ± 1·01. The renal clearance of S during the first day was twice as high as on the following days for two of the six volunteers (8 vs 4 ml min−1). The renal clearance of N4 during the first day, for four out of the six volunteers, was twice as high as on the following days (8 vs 4 ml min−1). The protein binding of S is 95 per cent and that of its conjugate N4 98 per cent. Approximately 80 per cent of the oral dose of S is excreted in the urine as parent drug (41·0 ± 6·2 per cent) and as N4 acetyl conjugate (39·9 ± 8·0 per cent).
A pharmacokinetic and tolerance study of romazarit in patients with rheumatoid arthritis
Authors: Williams P. E. O. , Bird H. A. , Minty S. , Helliwell P. S. , Muirhead G. J. , Bentley J. , York A.
Published: October 2006

Romazarit is a new drug for which animal pharmacology suggests a disease‐modifying action in rheumatoid arthritis (RA). These animal studies predict that plasma romazarit concentrations within the range 50–100 mg l−1 may be required for efficacy in the clinic. Therefore, a pharmacokinetic study was designed to estimate the dosage required to achieve these concentrations in man. Twenty‐four patients with RA entered a doubleblind controlled assessment receiving either placebo, 100 mg t.i.d., 350 mg b.i.d., or 350 mg t.i.d., for 6 days. Pharmacokinetic profiles were measured after single doses and after the last of the multiple doses. Adverse events were mainly trivial and were distributed almost equally between all three treatment and the placebo groups. Plasma romazarit concentrations were not dose‐proportional after the single doses. Mean peak plasma drug concentrations were 11·8, 66·7, and 159 mg l−1 at steady state after 100 mg t.i.d., 350 mg b.i.d., and 350 mg t.i.d. The mean urinary recovery of drug‐related material (mostly ester glucuronides) was 71 per cent of the dose during the dosage interval. The renal clearance of romazarit glucuronides correlated with creatinine clearance (p<0·01). Saturable tubular secretion of glucuronides coupled with reversible glucuronidation would explain these findings. It is predicted that oral doses of 450 mg romazarit given 12‐hourly will result in plasma concentrations within the target range of 50–100 mg l−1.
Brain regional pharmacokinetics of biperiden in rats
Authors: Yokagawa Koichi , Nakashima Emi , Ishizaki Junko , Hasegawa Mitsuru , Kido Hideki , Ichimura Fujio
Published: October 2006

The pharmacokinetic profiles of biperiden (BP) in blood and in specific brain regions were investigated in rats after acute i.v. administration. The regional brain‐to‐blood unbound concentration ratios (Kpf) were also determined after 16h intravenous infusion of BP. The Kpf values ranged from 30 to 75 in the different brain regions and showed decreasing concentrations in the following order: pons + medulla oblongata, basal ganglia, amygdala, hypothalamus, thalamus, mesencephalon, bulbus olfactorius + septum, hippocampus, frontal cortex, occipital cortex, cerebellum. The relationship between BP and acetylcholine (ACh) concentrations in the brain regions was examined. ACh levels in the various brain regions ranged from 8 to 44 ng g−1 tissue. There was a significant correlation between the Kpf values of BP and the levels of ACh in the brain regions except for the pons + oblongata. BP concentrations in the brain regions after BP administration were predicted based on the physiological pharmacokinetics. There was reasonable agreement between the model predictions and the observed data.
A simplified approach for evaluation of hepatic drugoxidizing activity with a simultaneous determination of caffeine and trimethadione and their demethylated metabolites in rats with a selective cytochrome P‐450 inducer
Authors: Tanaka Einosuke , Ishikawa Akio , Yamamoto Yuji , Uchida Eiji , Kobayashi Shinichi , Yasuhara Hajime , Misawa Shogo
Published: October 2006

We determined the blood concentrations of caffeine (CA) and its three primary dimethylxanthine metabolites: theobromine (TB), paraxanthine (PX), and theophylline (TP), and trimethadione (TMO) and its demethylated metabolite dimethadione (DMO) after the simultaneous administration of CA (10 mg kg−1) and TMO (4 mg kg−1) to rats pretreated with phenobarbital (PB: 40 and 80 mg kg−1 i.p. daily for 3 days) and 3‐methylcholanthrene (MC: 10 and 20 mg kg−1 i.p. daily for 2 days). After the oral administration of CA and TMO, the PB‐pretreated rats showed a significant increase in TMO metabolism, whereas the CA metabolism was greatly accelerated in rats pretreated with MC.

In five pretreated groups, there were correlations which were determined 1 h after the administration of CA and TMO, between the plasma half‐life (t1/2) of CA and the TB/CA, PX/CA, and TP/CA ratios. The coefficients of correlation (r) ranged from −0·881 to −0·908, and the coefficients of correlation between the CL of CA and the TB/CA, PX/CA, and TP/CA ratios ranged from 0·959 to 0·989.

There were high correlations between the t1/2 of TMO and the DMO/TMO ratio at 1 h after administration with r = −0·966, and between the CL of TMO and the DMO/TMO ratio with r = 0·971.

The above results suggest that one blood sampling after the simultaneous administration of CA and TMO enables prediction of the degree of each hepatic drug‐oxidizing activity because the P‐450 isozymes involved in metabolism of CA and TMO are different.
Plasma disposition and hemo‐dynamic effects of a single oral dose of isosorbide dinitrate in human males and females
Authors: Nakatsu K. , Brien J. F. , Savard G. , Toffelmire E. B. , Abdollah H. , Bennett B. M. , Marks G. S.
Published: October 2006

The goal of the present work was to determine the plasma disposition and hemo‐dynamic effects of isosorbide dinitrate (ISDN) in human males and females. Fourteen healthy human volunteers took part in the study; seven males, 21·7±2·5 y (SD), and seven females, 20·7±3·4 y. Measurements of forearm blood flow (FBF), vascular conductance (FVC), and venous capacitance (Cv) were obtained by venous occlusion plethysmography, whereas blood pressure was measured by automatic sphygmo‐manometry. Blood samples were taken through a catheter placed in the antecubital vein at 0, 15, 30, 45, 60, 90, 120, 360, 480, 720, and 1440 min following a single 10 mg oral dose of ISDN. Plasma concentrations of ISDN and its mononitrate metabolites, isosorbide‐2‐mononitrate (2‐ISMN) and isosorbide‐5‐mononitrate (5‐ISMN), were determined by large bore capillary column gas—liquid chromatography. Hemodynamic measurements were made at corresponding experimental times up to 480 min. No differences were observed in the disposition of ISDN, 2‐ISMN or 5‐ISMN between the male and female volunteers. In addition, the plasma concentrations of ISDN and its mononitrate metabolites did not consistently correlate with the hemodynamic changes of the individual subjects. Diastolic blood pressure was significantly decreased for a 0·5h period starting at 30 min, which was the time at which plasma ISDN concentrations peaked, and which preceded the time when the plasma concentrations of 2‐ISMN and 5‐ISMN were maximal. These observations indicate that, for a single 10mg oral dose of ISDN, there were no gender‐dependent differences in the plasma disposition of the parent drug or its mononitrate metabolites, and the vascular changes responsible for the decrease in diastolic blood pressure in these volunteers occurred in vascular beds other than those of skeletal muscle as represented by forearm blood flow.
Distribution of carbamazepine and its epoxide in blood compartments in adolescent and adult epileptic patients
Authors: Bonneton J. , Genton P. , Mesdjian E.
Published: October 2006

Carbamazepine (CBZ) used in the treatment of epilepsy, is metabolized in man to an active metabolite: carbamazepine 10–11 epoxide (CBZ‐E). CBZ and CBZ‐E concentrations in the different blood compartments (plasma ultrafiltrate, plasma proteins, and red blood cells (RBC)) of epileptic patients on CBZ monotherapy were assessed using HPLC. The highest CBZ and CBZ‐E level to dose ratios were observed in the RBC. For CBZ and CBZ‐E significant correlations were found between some blood compartments particularly between RBC and plasma ultrafiltrate. The measurement of CBZ and CBZ‐E in all blood compartments may be interesting in uncontrolled patients and in patients presenting side‐effects which cannot be explained by total plasma concentration values.
Applicability of teicoplanin dosage adjustment guidelines for renally impaired patients over the range of 3 to 30MGKG−1
Authors: Smithers Jacquelyn A. , Thompson Gary A. , Kenny Michael T. , Dulworth Jacqueline K. , Kulmala Henrik K. , Lewis Eric W. , Ruberg Stephen J. , Shapiro Bruce E. , Keane William F. , Halstenson Charles E.
Published: October 2006

The pharmacokinetics of teicoplanin were investigated in 13 subjects with various degrees of renal impairment using a randomized two‐period crossover design; 11 subjects completed both periods. Doses of 3 and 30 mg kg−1 were administered as single dose, 60‐min constant rate intravenous infusions. Blood samples were obtained over 28 days and urine was collected over 48 h. Serum and urine were analyzed using a microbiological assay. As previously observed in studies conducted in renally impaired subjects, teicoplanin total and renal clearance significantly decreased with decreasing creatinine clearance (p<0·0001). However, for these parameters, no differences between doses were observed. Dosage adjustment guidelines for renally impaired patients are usually developed using the ratio of total clearance in renally impaired patients to the total clearance in patients with normal renal function. Since no dose‐related differences existed in the relationship between teicoplanin total clearance and creatinine clearance, initial dosage adjustment guidelines for renally impaired patients developed at 3 or 30 mg kg−1 are applicable over the range of 3 to 30 mg kg−1.
Sex‐differences in the disposition of substituted benzamides: Pharmacokinetics of a gastroprokinetic agent (4‐amino‐5‐chloro‐2‐[2‐(methylsulfinyl) ethoxy]‐N‐[2‐(diethylamino)ethyl] benzamide hydrochloride) (ML‐1035) in male and female New Zealand white rabbits
Authors: Rao Niranjan , Otis Kenneth W , Hwang Kin‐Kai
Published: October 2006

The disposition of 4‐amino‐5‐chloro‐2‐[2‐(methylsulfinyl)ethoxy]‐N‐[2‐(diethylamino) ethyl] benzamide hydrochloride (ML‐1035) following intravenous (10 mg kg−1) and oral (200 mg kg−1) dosing was investigated in male and female New Zealand white rabbits. After intravenous dosing ML‐1035 was eliminated with a half‐life of 1·45 ± 0·49 h in males and 0·79 ± 0·08 h in females. Volume of distribution at steady‐state was 2·08 ± 0·98 1 kg−1 in males and 9·11 ± 5·86 1 kg−1 in females. Clearance averaged 2·99 ± 1·11 1 h−1 kg−1 in males and 16·73 ± 7·29 1 h−1 kg−1 in females. All pharmacokinetic parameters were significantly different between males and females (p<0·05). Absolute bioavailability after oral administration was 7·35 per cent for males and 12·31 per cent for females, suggesting that ML‐1035 undergoes significant first‐pass elimination. Plasma area under the curve for the metabolites of ML‐1035 after both oral and intravenous administration were also different between the two sexes. These data suggest that the disposition of ML‐1035 shows significant differences between male and female rabbits.
In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCl
Authors: Caramella C. , Ferrari F. , Bonferoni M. C. , Sangalli M. E. , Di Valserra M. De Bernardi , Feletti F. , Galmozzi M. R.
Published: October 2006

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non‐disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus.

The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and td of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and td between 149 and 291 min.

The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half‐life t1/2 (7.12 h), while apparent t1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for Cmax and AUC values, and no relationships could be established with the type of formulation.

An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p <0.05).

In a few cases the Wagner‐Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the ‘Levy's plot’ (per cent released versus per cent absorbed) approach and provided further support for the correlation found.
Influence of food on the disposition of the monoamine oxidase‐A inhibitor brofaromine in healthy volunteers
Authors: Degen P. H. , Cardot J. M. , Czendlik C. , Dieterle W.
Published: October 2006

The effect of food on the bioavailability of brofaromine hydrochloride was investigated in a randomized cross‐over study. Eight healthy male volunteers were given single peroral doses of 75 mg brofaromine hydrochloride after overnight fasting or a fat‐ and proteinrich breakfast. Mean (± SD) areas under the plasma concentration‐time curves (AUC) were 9.66 (2.35) μmoll−1 h when given to the fasted volunteers and 11.82 (3.78) μmoll−1 h (p = 0.0413) when given after a substantial breakfast. Mean (± SD) maximum plasma concentrations (Cmax) were 0.71 (0.13) μmoll−1 when given to the fasted volunteers and 0.85 (0.22) μmoll−1 (p > 0.05) when given after breakfast. Thus, both the average AUC and Cmax were increased by approximately 20 per cent when brofaromine hydrochloride was given with food. The times when Cmax was reached (tmax) as well as the elimination half‐lives were not influenced by concomitant intake of food. The tolerability was the same whether brofaromine was given before or after food in healthy volunteers. The slight effect of food on the bioavailability of brofaromine should be of little therapeutic consequence because of the observed wide inter‐subject variability of the plasma levels.
Pharmacokinetics of the new antiasthma and antiallergy drug, azelastine, in pediatric and adult Beagle dogs
Authors: Adusumalli V. E. , Wichmann J. K. , Wong K. K. , Kucharczyk N. , Sofia R. D.
Published: October 2006

The plasma concentrations and relative bioavailability of azelastine hydrochloride (AZ) and its desmethyl metabolite (DAZ) after a single and 10 once‐a‐day oral doses of 2.5 mg kg−1 AZ were determined in adult male and female and pediatric male and female beagle dogs. The pediatric and adult dogs were 4–6 weeks and 1–2 years of age, respectively. An analysis of variance (ANOVA) was performed on the bioavailability parameters among all groups and between the first and last doses. No statistically significant (p <0.05) sex‐related differences in the bioavailability parameters were observed. The peak concentration (Cmax) of AZ, especially after the first dose, was significantly higher in pediatric dogs than that in adult dogs, whereas following the multiple AZ administrations, the bioavailability parameters for the last dose were similar in the two age groups. The apparent volume of distribution (Vss) of AZ suggested that the drug was extensively distributed into tissue in adult as well as in pediatric dogs. The Vss was considerably smaller in pediatric dogs, which may explain the higher Cmax in this age group. The bioavailability of the metabolite in adult dogs after multiple administration of AZ was higher than that in pediatric dogs. Although some differences in the parameters among the groups are statistically significant, they do not appear to have any biological significance. Therefore, similar AZ dosages may be required in pediatric and in adult populations to achieve optimum therapeutic drug levels.
Disposition of SK&F L‐190144 in rats and monkeys after oral, intravenous or ocular administration
Authors: Tang‐Liu Diane D‐S. , Richman Joseph B. , Lin Paul , Selim Sami
Published: October 2006

The objective of the study was to investigate the systemic disposition of 14C‐SK&F L‐190144 after single intravenous (10mg kg−1) and oral (200 mg kg−1) doses to rats and after single intravenous and ocular doses (0.33 mg kg−1) to monkeys.

After the intravenous dose, the blood concentration‐time profile of 14C‐SK&F L‐190144 followed a rapid triexponential decline with half‐lives of 2.5, 15, and 246 min in rats and 3, 19, and 2520 min in monkeys. The 14C‐label in blood was mainly the parent compound. The terminal elimination half‐life detected in rats using the urinary excretion rate‐time data was 700 min. The total body clearance values were 17.6 ± 2.1 (mean ± SD, n = 6) and 1.11 ± 0.41 (n=4) mlmin−1 kg−1 for rats and monkeys, respectively. Both species had similar values of volume of distribution at the terminal phase, 4 to 6 l kg−1, and similar excretion patterns, approximately 60 per cent and 30 per cent of the dose were excreted in the urine and feces, respectively.

14C‐SK&F L‐190144 was not absorbed orally in rats with the majority of the dose recovered in the feces. Following ocular administration to monkeys, the plasma drug concentrations peaked at 8 h post‐dosing but did not reach a biexponential elimination phase until 18 h post‐dosing, suggesting slow systemic absorption of drug from the ocular site. The monkeys excreted 42 per cent of the dose in urine and 50 per cent in feces after ocular administration. This increase in fecal excretion compared to the intravenous route of administration may have been due to the slow absorption by the ocular and nasal tissues altering the relative proportions of drug elimination via the renal and hepatic routes, or to a proportion of the dose passing into the gastrointestinal tract and exiting unabsorbed.

Study results demonstrate similar excretion patterns and volume of distribution after intravenous administration in both species. The slow terminal elimination phase in monkeys was attributed to the low body clearance. The low oral bioavailability was possibly due to the poor partitioning behavior of the drug (logarithm of partition coefficient ‐ 2.6). A significant fraction of the dose was absorbed in the body via the ocular route.