bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro and in vivo evaluation of seven 50 mg and 100 mg nitrofurantoin tablets
Authors: Meyer Marvin C. , Wood George C. , Straughn Arthur B.
Published: October 2006

Four 50 mg and three 100 mg marketed nitrofurantoin tablets were studied in 14 healthy male subjects. Urine was collected 1, 2, 3, 4, 6, 8, 12, and 23 h after each dose, and nitrofurantoin was assayed by HPLC. The in vitro dissolution of the tablets was determined using USP Apparatus 1 and 2, with 0·1 N hydrochloric acid and pH 7·2 buffer as the dissolution fluids. One of the 50 mg tablets was more rapidly and completely absorbed than the other six products. The incidence of side‐effects for this product was as low or lower than the other products. It was determined that the use of the USP Apparatus 1, at 100 rev min−1, with sampling of the pH 7·2 fluid at 30 min, provided for the best overall relationship between the urinary excretion and in vitro dissolution.
Buffering the stomach content enhances the absorption of diflunisal in man
Authors: Nuernberg Bernd , Brune Kay
Published: October 2006

Diflunisal, a lipophilic salicylate, is absorbed more slowly in healthy volunteers than aspirin. In this paper we report on attempts to influence diflunisal absorption by buffering the gastric milieu. Sodium bicarbonate given together and 30 min after diflunisal tablets significantly (p < 0·05) shortened the time to reach peak plasma concentration (tmax > 15 per cent), raised maximum plasma concentration slightly (Cmax 6 per cent) and increased the area under the plasma concentration‐time curve (AUC > 8 per cent). Other pharmacokinetic parameters, including terminal half‐life and renal elimination of the compound, were not considerably influenced. These findings indicate that the absorption of diflunisal was enhanced by increased gastric pH, presumably a result of an increased solubility of diflunisal in the stomach together with faster transport into the small intestine.

In one volunteer, after intravenous administration diflunisal plasma concentrations declined in a triphasic manner with a terminal half‐life of 12·8 h. The volume of distribution was approximately 10 per cent of body weight. Based on the ratio of AUC after equivalent i.v. and oral diflunisal doses, the absolute bioavailability was 89·5 per cent.
Gastrointestinal, liver, and lung extraction ratio of acetaminophen in the rat after high dose administration
Authors: Bhargava v. O. , Hirate Junji
Published: October 2006

The pharmacokinetics of acetaminophen was examined in rats after administration of a single dose of 200 mg kg−1 by the intra‐arterial, intravenous, portal vein, and oral routes. Levels of acetaminophen and its two major metabolites, acetaminophen‐glucuronide and acetaminophen‐sulfate, were quantitated in plasma at various time points for about 5 h after drug administration. The relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction ratio (first‐pass effect after oral absorption) was determined. A mean oral extraction ratio of 0·49 was obtained. The mean relative extraction ratio of the gastrointestinal tract, liver, and lung were 0·52, 0·07, and 0, respectively, indicating a major contribution due to the gastrointestinal tract. This is in contrast to earlier studies which have indicated negligible contribution by the gastrointestinal tract to the oral first‐pass effect when lower doses were utilized. These results suggest that the relative contribution of the gastrointestinal tract and liver to the oral first‐pass effect of acetaminophen may be dose‐dependent.
Pharmacokinetics of lisinopril (IV/PO) in healthy volunteers
Authors: Beermann Bjorn , Till Alice E. , Gomez Hector J. , Hichens Martin , Bolognese James A. , Junggren Inga‐Lill
Published: October 2006

When three intravenous doses of lisinopril were administered to healthy volunteers, area under the curve (to infinity) vs dose was linear with a positive intercept. Subtracting area under the extrapolated terminal phase of the serum profile from zero to infinity retained the linear relationship, but shifted the regression line to a zero intercept. It is postulated that the terminal phase reflects binding of drug to angiotensin‐converting enzyme (ACE). The half‐life for the terminal phase (approximately 40 h) was not predictive of steadystate parameters when ten daily doses (q24h) of lisinopril were administered orally to healthy volunteers. The mean effective half‐life for accumulation was 12·6h. The mean accumulation ratio was 1·38. Steady state was attained after the second daily dose. The observations in these studies with lisinopril are similar to those reported for enalaprilat, the active metabolite of the ACE inhibitor, enalapril maleate.
Mean residence time: Some further consideration
Authors: Collier Paul S.
Published: October 2006

The correct use of probability distribution functions is described for the determination of mean residence time (MRT) of drug molecules in the body and is illustrated for two possible two compartment body models. A new method for estimating (MRT) is described, based on the area under the curve measurement for the decay of drug from steady state.
Competitive binding of sulfamethazine and its N‐acetylated metabolite
Authors: Tsang Y‐C. , Thiessen J. J.
Published: October 2006

The protein binding of sulfamethazine (SMZ) was studied in rabbit serum. Serum solutions comprising various concentrations (∼0·01 – 3mM) of SMZ and its major metabolite, N4‐acetylsulfamethazinc (AcSMZ), were prepared. These ‘control’ samples were also mixed via a Latin square design to study the interactive binding of SMZ and AcSMZ to the proteins. Equilibrium dialysis was conducted for 8 h.

Post‐dialysis measurement of SMZ/AcSMZ radioactivity in the buffer and serum chambers provided the free and bound fractions based upon equilibrium total serum concentrations. There was no significant change of protein concentration before and after dialysis. The ‘control’ data revealed concentration‐dependent binding for both drugs while the interaction study clearly indicated the presence of competitive binding. Scatchard plots suggested the presence of more than one binding site. As a result, three different competitive binding models were examined via computer analysis of the observations. The most appropriate binding model was identified to consist of specific binding (protein concentration, Pt; dissociation constant, Kd) and nonspecific binding (Nsp). The mean (SD) ‘control’ parameter estimates for PtSMZ, PtAcSMZ, KdSMZ, KdAcSMZ, NspSMZ, NspAcSMZ were: 0·562(0·041), 0·605(0·024), 0·078(0·006), 0·031(0·002) [mM], 0·205(0·054), and 0·229(0·043), respectively. In the interaction study these values were: 0·599(0·022), 0·479(0·019), 0·091(0·004), 0·023(0·001), 0·228(0·020), and 0·434(0·061), respectively. The findings indicate that both drugs bind to albumin but the affinity of AcSMZ is greater than SMZ. Theoretically, the metabolite can therefore alter the in vivo SMZ binding thereby in turn causing apparent nonlinear acetylation based upon the pharmacokinetics of total SMZ concentrations.
Relationships between steady‐state and single‐dose plasma drug concentrations for pharmacokinetic systems with nonlinear elimination
Authors: Cheng Haiyung , Jusko William J.
Published: October 2006

Equations were examined to predict or correlate steady‐state (SS) plasma concentrations and single‐dose (SD) data for pharmacokinetic systems with various types of input and nonlinear elimination. The effects of variation of the Michaelis‐Menten parameters, input rate of drug, or bioavailability on the predictability of steady‐state plasma concentrations from single‐dose data were demonstrated by computer simulations for a one‐compartment model. Use of apparently linear equations with Michaelis‐Menten parameters to predict steady‐state plasma concentrations from single dose data is adequate only in limiting low single‐dose cases. Linear SS versus SD correlations for both intravenous and oral dosing can be observed in population data only when Km is the principal variable; other conditions produce curvilinear behavior. Equations to calculate values of the Michaelis‐Menten parameters from dual single‐dose and steady‐state AUC values are derived and tested for drugs which are intravenously administered. These equations and simulations provide insight into factors determining the relationship between SS and SD AUC for drugs with nonlinear elimination.
Stability, human blood distribution and rat tissue localization of promazine and desmonomethylpromazine
Authors: Hu Oliver Y‐P. , Curry Stephen H.
Published: October 2006

The stability in human blood and urine, partitioning into red blood cells and plasma protein binding of promazine and desmonomethylpromazine were investigated. Tissue localization was investigated in rats. Promazine and desmonomethylpromazine were stable in human plasma and urine for at least 64 days at −20°. The percentage of promazine not bound to protein in plasma was 10·4 ± 2·43 as estimated by equilibrium dialysis with correction for volume shift, and 11·6 ± 0·43 per cent as estimated by ultracentrifugation. Data for the mean plasma/red blood cell concentration ratio and the red blood cell/plasma distribution coefficient for promazine were 1·19 ± 0·13 and 8·21 ± 0·40, respectively. There was no evidence of time‐dependence in plasma/red blood cell partitioning. Ten rat organs and tissues were examined. The concentrations of promazine and desmonemethylpromazine were highest in lung. For promazine, the rank order of tissue localization was lung > liver > kidney > intestine > brain > spleen > red blood cell > voluntary muscle > plasma > stomach > heart. For desmonomethylpromazine, the order was reversed in the cases of spleen and brain and interchanged in the cases of stomach and muscle. The brain/plasma concentration ratios for promazine and desmonomethylpromazine in rat were 4·69 and 3·87, respectively.
Effects of obesity and ancillary variables (dialysis time, drug, albumin, and fatty acid concentrations) on theophylline serum protein binding
Authors: Shum Linyee , Jusko William J.
Published: October 2006

The effect of obesity on the serum protein binding of theophylline was investigated in man and rat along with other ancillary variables such as dialysis time, theophylline concentration, albumin concentration, and fatty acid type and concentration. The per cent binding of theophylline first increased with dialysis time, reached equilibrium over 2 to 6 h, then diminished. This decrease was not due to instability of theophylline. Theophylline binding was linear over a concentration range of 15 to 150 μg ml−1. A similar degree of binding was found in normal humans (44·4 ± 1·0%) and rats (41·5 ± 0·5%). The binding ratio (bound/free) of theophylline was proportional to the albumin concentration (1 to 5%) and yielded a binding parameter (NK) of 1·47 × 10−3 M−1. Over a normal physiological range, individual and mixed fatty acids had minimal effects on theophylline binding to albumin. However, binding significantly decreased as fatty acid (FFA) concentrations increased. The magnitude of the effect appeared to parallel the carbon chain number of the fatty acid. Theophylline binding in obese subjects decreased to a mean (SD) of 35·8 ± 8·0 per cent compared to 43·0 ± 6·1 per cent in normal subjects (p < 0·05). Similar decreases were found in normal versus obese rats and in the saliva: serum ratio following theophylline administratin to normal and obese human subjects. Obesity causes a moderate decrease in serum binding of theophylline which may be attributed to increased FFA rather than in vitro artifacts.
Bioinequivalence of a generic brand of diazepam
Authors: Locniskar Ann , Greenblatt David J. , Harmatz Jerold S. , Shader Richard I.
Published: October 2006

Twenty‐six healthy male volunteers received a single 10 mg dose of diazepam on two occasions in a crossover bioequivalence study comparing the reference product (Valium) and a generic formulation (NeoCalme). Concentrations of diazepam and its metabolite, desmethyldiazepam, were determined during 264 h after each dose. Peak plasma diazepam concentrations were significantly lower for NeoCalme vs Valium (247 vs 394 ng ml−1, p < 0·001) and reached significantly later after the dose (1·62 vs 0·98 h, p < 0·001). Total area under the plasma concentration curve (AUC) was also significantly lower for NeoCalme (6614 vs 7552 ng ml−1 × h, p < 0·001), although AUC ratios for NeoCalme divided by Valium satisfied the ‘75–75’ guidelines. Findings for desmethyldiazepam were similar. Thus, diazepam absorption from the generic brand of diazepam is significantly slower than from Valium, which in turn could lead to therapeutic inequivalence.
Absorption and disposition kinetics of chlorothiazide in protein‐calorie malnutrition
Authors: Jung Donald , Lam Hue Di , Chu Michael
Published: October 2006

The influence of dietary protein deficiency on the absorption and disposition kinetics of chlorothiazide was investigated in male Sprague‐Dawley rats fed for 4 weeks on a 23 per cent (control) or a 5 per cent (low) protein diet ad libitum. Chlorothiazide in plasma and urine was determined by a sensitive and specific HPLC assay. Following an intravenous dose of 10mgkg−1 chlorothiazide, there was a significant decrease in the total plasma clearance (Cl) per kg of body weight from 1·80 ± 0·15 to 1·29 ± 0·15 1 h−1 kg−1 and apparent steady‐state volume of distribution from 0·65 ± 0·13 to 0·38 ± 0·071 kg−1 in the protein‐deficient rats. However, no significant difference was found in the two groups of animals with respect to mean residence time (MRT) and free fraction of drug in plasma. The mean harmonic half‐life was increased from 72 to 91 min in the protein‐deficient rats. The urinary recovery of unchanged chlorothiazide in 48 h was essentially complete in both groups of animals. The absorption of chlorothiazide, as assessed by the mean urinary recovery of unchanged drug after oral administration, was 66 per cent and 68 per cent in normal and protein‐deficient rats, respectively.
A new approach to pharmacokinetic parameters: Estimation of cefuroxime during haemodialysis
Authors: Sanchez Esther , Evora Carmen Ma , Torres Armando , Llabres Matias
Published: October 2006

A linear three‐compartment model is proposed as a means of estimating disposition and extracorporeal elimination pharmacokinetic parameters during haemodialysis. It was created by connecting a compartment, corresponding to the amount of drug present in the dialysis cell, to the central compartment of the standard two‐compartment model from which elimination would normally take place. The transfer rate constants between the central compartment and the ‘dialysis cell’ and vice versa were given in terms of the plasma flow, central compartment volume, and volume of plasma contained in the dialysis cell, and thus cannot be considered to be independent parameters. The product of the rate constant for elimination from the dialysis cell, k30, and the plasma volume within the cell was used to quantify the extracorporeal elimination and termed intrinsic dialyser clearance, CLint,D. The model was used to interpret the plasma level curves obtained after administering 750 mg cefuroxime by IV bolus to a group of patients undergoing haemodialysis. The distribution parameters estimated by non‐linear regression were similar to those given in the literature; however, in five of the twelve cases, no estimate of cefuroxime elimination from the central compartment (k10) could be derived. On the other hand, the estimates of the elimination rate constant (k30) from the deep peripheral compartment were greater than the values given in the literature, ranging from 50·6 h−1 to 151·0 h−1 and CLint,D ranging from 3·1 h−1 to 8·90 lh−1.

The error in measuring the flow of plasma which reaches the dialyser, its influence upon the estimation of the model parameters and the relationship between the parameters themselves and those customarily used in the study of drug haemodialysis are all discussed.
Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration
Authors: Scavone Joseph M. , Luna Becki G. , Harmatz Jerold S. , von Moltke Lisa , Greenblatt David J.
Published: October 2006

Eight healthy volunteers received 50 mg of dimenhydrinate, a theoclate salt of diphenhydramine, orally, sublingually, and intravenously on three separate occasions in random sequence. Plasma diphenhydramine concentrations during 12 h after each dose were measured by gas‐liquid chromatography with nitrogen‐phosphorous detection. Mean peak plasma concentrations after sublingual administration were slightly lower than after oral dosage (38·3 vs 47·8 ng ml−1), and the time of peak concentration was similar (2·6 vs 2·3 h after dose). These differences did not reach statistical significance. The mean total area under the plasma concentration‐time curve (AUC) for sublingual administration was slightly but not significantly smaller than after oral dosage (221 vs 270 h ng ml−1). Systemic availability of diphenhydramine after sublingual dimenhydrinate, measured by the ratio of oral AUC to intravenous AUC, was slightly less than after oral dimenhydrinate (0·58 vs 0·69, NS), and both were significantly less than 1·0. Thus sublingual and oral administration of dimenhydrinate result in comparable, but incomplete, systemic availability of diphenhydramine.
Intramuscular administration of atropine in the rat: Jet spray versus conventional needle injection
Authors: Lieske Claire N. , Lukey Brian J. , Hayward Isaac J. , Gepp Robin T. , Meyer Howard G.
Published: October 2006

The characteristics of atropine plasma levels after jet spray injection were compared to those after conventional needle injection (i.m.) in 12 male rats, six per group. Blood samples were sequentially collected from the tip of the tail over a 7h period. Injection of atropine sulfate (8.0mgkg−1) using the jet spray resulted in mean peak plasma levels of 650ngml−1 (95 per cent C.I. = 90) compared to 488ngmg−1 (95 percent C.I. = 64) using a conventional needle. Times to reach maximum concentration were 30min (95 per cent C.I. = 12) and 58min (95 per cent C.I. = 6) for the jet spray and needle, respectively. Histopathologic examination (5 days post‐injection) of target muscle showed that minimal fiber damage resulted from using the low pressure setting on the jet spray. The results suggest that the jet spray may offer a means of increasing the antidotal benefit over that achieved with conventional techniques using presently available therapeutic formulations for acetylcholinesterase poisoning.
Effects of dose and sex on the pharmacokinetics of piroxicam in the rat
Authors: Roskos Lorin K. , Boudinot F. Douglas
Published: October 2006

The effects of dose and sex on the pharmacokinetics of piroxicam were studied in the rat. Piroxicam was administered intravenously at doses of 0.50 and 5.0 mg kg−1 to male and female rats. Plasma drug concentrations were determined by a highly sensitive high‐performance liquid chromatographic technique. Non‐compartmental pharmacokinetic parameters were calculated by area/moment analysis. A prolonged terminal half‐life averaging 13.3 h in male rats and 40.8 h in female rats was observed. Dose had no effect on the disposition of piroxicam. The sex of the rat, however, had a marked effect on piroxicam pharmacokinetics, with mean total clearance differing three‐fold from 0.01841 h−1 kg−1 in male rats to 0.00622 1 h−1 kg−1 in female rats. The free fraction of piroxicam in serum was greater in male rats than in female rats owing to a higher association constant for piroxicam binding to female rat serum proteins. Free piroxicam clearance differed approximately two‐fold with mean values of 0.764 1 h−1 kg−1 and 0.418 1 h−1 kg−1 in male and female rats, respectively. Thus, protein binding partially explained the sex‐dependent disposition of piroxicam. However, sex‐dependent metabolism of the drug also appears to be a major determinant of sex‐related differences in piroxicam pharmacokinetics. Steady‐state volume of distribution was unaffected by sex. Half‐life and mean residence time were three‐fold greater in female rats owing to the three‐fold lower clearance value compared to male rats.
Pharmacokinetic and pharmacodynamic studies in man with an antianginal agent ‘Visacor’
Authors: Cockshott Ian D. , McAinsh James , Norris Stephanie
Published: October 2006

This randomized, double‐blind, crossover study in 10 healthy male volunteers compared four single oral doses of ICI 141,292 (‘Visacor’), i.e. 50, 100, 200, and 300 mg, with placebo. Venous blood samples were collected pre‐dose and at various times after dosing and the concentrations of ICI 141,292 in the plasma were determined by radioimmunoassay. A standardized 4‐min bicycle exercise test was also performed and before this the resting haemodynamic parameters were assessed.

Peak plasma concentrations of ICI 141,292 and the area under the plasma concentration–time curve increased disproportionately with dose such that after scaling to a dose of 200 mg there remained a significant linear trend with dose. The time to peak plasma concentration displayed an increasing trend with dose and, once again, the linear component of this trend was statistically significant. The mean heart rates during exercise were all significantly reduced compared to placebo for 24 h by each of the doses (range 7·8 to 17·4 beats min−1 at 24 h, p <0·01). The increase in heart rate during exercise was inversely related to the logarithm of the ICI 141,292 plasma concentration with higher plasma concentrations being associated with lower heart rate increases. The mean supine resting heart rates were slightly but significantly reduced at 2 and 6 h after dosing by each treatment and by the 300 mg dose at 24 h. Each of the doses of ICI 141,292 was well tolerated.
Pharmacokinetic aspects of the sublingual administration of vincamine
Authors: Aiache J‐M. , Delatte M‐C. , Leblanc P‐P. , Kantelip J‐P. , Steimer J‐L.
Published: October 2006

The sublingual absorption of vincamine used as tracer occurs in two successive absorption steps: true sublingual absorption and absorption in the gastrointestinal tract of the drug dissolved in the saliva and not absorbed through the buccal mucosa. This is confirmed by a pharmacokinetic study and simulation. These two successive absorptions can explain the increase in the amounts of drug absorbed.
Analysis and stereoselective metabolism after separate oral doses of tocainide enantiomers to healthy volunteers
Authors: Hoffmann Kurt‐Jürgen , Renberg Lars , Gyllenhaal Olle
Published: October 2006

The potential of stereoselective metabolism of tocainide was studied in six healthy volunteers after separate oral administration of the pure enantiomers in solution. A method was developed to convert the N‐carbamoylglucuronide of tocainide in plasma and urine by base treatment to a hydantoin derivative which after extraction and silylation was analysed by selected ion monitoring using a deuterated internal standard. Analytical problems concerning side‐reactions during derivatization of the conjugate are discussed.

The peak plasma levels of the enantiomers, observed at ≦2 h after dosing, were similar but plasma clearances and terminal half‐lives were different after oral administration of (R)‐tocainide (195.5 ± 20.1 ml min−1 and 9.7 ± 0.8 h) and (S)‐tocainide (110.2 ± 10.5 ml min−1 and 14.5 ± 1.7 h). Over 0–96 h the averaged urinary recovery of (R)‐tocainide was 36 per cent and of (S)‐tocainide 50 per cent. Stereoselective metabolism was a likely mechanism for the observed differences as the urinary recovery of the conjugate formed from (R)‐tocainide differed substantially from that of (S)‐tocainide (45 vs 1.2 per cent of given dose). Plasma t1/2 of the (R)‐ and (S)‐conjugate were 9.9 and 18.7 h, respectively, indicating formation rate limited kinetics of the metabolite. The renal clearances of the conjugates were not significantly different (131 vs 97 ml min−1).
Effects of inducers and inhibitors of mixed‐function oxidases on the biliary excretion of pentacaine metabolites
Authors: Kukan M. , Bezek Š. , Ščasnár V. , Ďurišová M. , Trnovec T.
Published: October 2006

The biliary excretion of 3H‐pentacaine and its metabolites was studied in rats pretreated with an inducer or inhibitor of mixed‐function oxidases. Over one‐fourth (25·8 per cent) of a 2 mg kg−1 intraportal dose of 3H‐pentacaine was excreted in bile in urethaneanaesthetized control rats within 3 h. The radioactivity appeared in the form of the parent drug, basic metabolites, and metabolite conjugates, 3·1, 86·5, and 10·4 per cent of the total radioactivity excreted, respectively. Pretreatment of rats with phenobarbital enhanced only slightly the biliary excretion of basic metabolites, and pretreatment with 3‐methylcholanthrene had no effect. Phenobarbital also increased the initial rate of excretion of conjugates, but this effect was not sustained. 3‐Methylcholanthrene had a tendency to impair excretion of conjugates by bile. Pretreatment of rats with SKF 525‐A decreased the biliary excretion of both basic metabolites and conjugates while cimetidine did not alter significantly the biliary excretion of pentacaine metabolites. These results suggest that the canalicular transport of metabolites may be the most important factor in controlling pentacaine metabolite excretion in bile.
Kinetics of biliary elimination of pentacaine in rats
Authors: Bezek Š. , Ščasnár V. , Kukan M. , Trnovec T.
Published: October 2006

Pentacaine, a local anaesthetic of the carbanilate type, administered intravenously as 3H‐pentacaine, 2mg kg−1 to rats, was eliminated in the bile mainly in the form of metabolites (20·5 ± 1·5 per cent of the dose) and as parent drug (0·1 per cent of the dose) within 3 days. In control rats 32·2 ± 2·5 and 37·8 ± 2·5 per cent of 3H‐dose, representing pentacaine metabolites, were excreted in the urine and faeces, respectively. In bile‐ductucannulated rats 35·7 ± 6·8, 11·2 ± 3·4, and 20·5 ± 1·5 percent of 3H‐dose were excreted in the urine, faeces, and bile, respectively. The high 3H recovered in faeces in animals with diverted bile flow indicated passage of pentacaine metabolites through the intestinal wall. The excretion of pentacaine and its metabolites in bile was an active process, since the ratio bile/plasma concentration rapidly attained values approaching 10. In rats with ligated ureters the biliary elimination of pentacaine and its metabolites was enhanced, compensating for impaired urinary excretion. This was accompanied by increased plasma and brain levels of 3H compared with untreated controls.
Disposition of fluvastatin, an inhibitor of HMG‐CoA reductase, in mouse, rat, dog, and monkey
Authors: Tse F. L. S. , Smith H. T. , Ballard F. H. , Nicoletti J.
Published: October 2006

The physiological disposition of fluvastatin, a potent inhibitor of hydroxymethylglutaryl‐CoA reductase and thus cholesterol synthesis, has been studied in the mouse, rat, dog, and monkey using 14C or 3H‐labeled drug. Oral doses of fluvastatin were absorbed at a moderate to rapid rate. The extent of absorption was dose‐independent and was essentially complete in all four species studied. However, the drug was subject to extensive presystemic hepatic extraction followed by direct excretion via the bile, thus minimizing the systemic burden and yielding high liver/peripheral tissue concentration gradients for fluvastatin and its metabolites. Only at high doses far exceeding the intended human daily dose of ca 0·6 mg kg−1 did fluvastatin bioavailability approach unity, apparently due to saturation of the first‐pass effect. Dose‐normalized blood levels of fluvastatin and total radioactivity were higher in the dog than in the other species, suggesting a smaller distribution volume in the former. Fluvastatin was partially metabolized before excretion, the extent of metabolism being smallest in the dog and greatest in the mouse. The half‐life of intact fluvastatin ranged from 1–2 h in the monkey to 4–7 h in the dog. Regardless of the dose or dose route, the administered radioactivity was recovered predominantly in feces, with the renal route accounting for less than 8 per cent of the dose. No tissue retention of radioactivity was observed, and material balance was essentially achieved within 96 h after dosing.
Pharmacokinetics of promazine: I disposition in patients with acute viral hepatitis B
Authors: Hu Oliver Y.‐P. , Tang Hung‐Shang , Sheeng Tuzen‐Yan , Chen Sung‐Chao , Lee San‐Kan , Chung Ping‐Hong
Published: October 2006

Concentrations of promazine in plasma, plasma water, red blood cells, and urine were measured after oral administration of the drug to six patients during and after apparent recovery from the acute phase of viral hepatitis B. None of the promazine pharmacokinetic parameters were significantly different during and after the acute phase; these parameters included clearance, free drug clearance, metabolic clearance, volume of distribution, distribution and elimination half‐life values, plasma protein binding, and per cent excreted in the urine. During the acute period of the illness, SGOP, SGPT, alkaline phosphatase, and total bilirubin were increased in all patients; they returned to within or near the upper limits or normal after recovery. Despite the unchanged promazine disposition, four out of six patients had more severe promazine side‐effects, such as sedation, postural hypotension, and dizziness during the acute phase of the illness. This study suggests that promazine disposition was not significantly altered as a consequence of viral hepatitis. However, the pharmoacodynamic effects of promazine were changed significantly. Care must be taken with patients who are taking promazine during the acute phase of viral hepatitis B.
Pharmacokinetics of pafenolol after IV and oral administration of three separate doses of different strength to man
Authors: Regårdh C. G. , Heggelund A. , Kylberg‐Hanssen K. , Lundborg P.
Published: October 2006

The pharmacokinetics of pafenolol were evaluated in 12 healthy subjects after administration of three single IV doses (5, 10, and 20mg) and three oral single doses (25, 50, and 100mg). The drug was discontinuously absorbed. A first peak was observed 0·5 to 1·5h after dosing and a second higher maximum concentration was noted 3 to 5h after the administration in the majority of the experiments. The mean systemic availability increased from 27 ± 5 per cent for the oral 25 mg dose to 46 ± 5 per cent for the 100mg dose, i.e., an increase of about 70 per cent (p < 0·05). The half‐life of distribution varied between 5 and 6min and the apparent volume of distribution (Vz) was about 1·11 kg−1. The distribution was linear in the IV dose range studied. Total body clearance was about 300ml min−1. About 50 per cent of the systemically available dose was excreted unchanged via the kidneys. Total body clearance decreased by about 13 per cent (p < 0·05) by increasing the dose from 5 to 20mg IV possibly because of reduced renal elimination. Mean terminal t1/2 of the IV dose was ∽ 3·5h. The corresponding t1/2 of the oral dose was ∽ 6h indicating absorption rate‐limited kinetics of the oral dose.
Regional pharmacokinetics I. physiological and physicochemical basis
Authors: Upton Richard N.
Published: October 2006

Systemic pharmacokinetics is the study of the time‐course of drug concentrations in ‘systemic’ blood sampled from either an arterial, central venous or peripheral venous blood vessel. It is generally not suitable for studying the pharmacokinetics of drugs in individual organs of the body, when the blood concentrations of a drug are changing rapidly, or when the physiological or pathophysiological status of a patient is unstable. Regional pharmacokinetics addresses some of these limitations and is based on the study of the factors influencing drug concentrations in specific regions (tissues, organs) of the body due to the movement of drug from blood into and out of the region (drug ‘uptake’ and ‘elution’, respectively). It provides a vital link between systemic pharmacokinetics and molecular pharmacology. The physiological basis of regional pharmacokinetics is a function of the interactions of the drug between the cells and proteins in blood, the blood flow supplying a region, the structure of the capillaries of the region and the types of specific and non‐specific binding within the region. The physicochemical basis of regional pharmacokinetics is a function of the factors influencing the rate and extent of diffusion of a drug through aqueous and lipid mediums, such as molecular weight, ionization, charge, and lipophilicity.
Pharmacokinetic modelling of the plasma concentration‐time profile of the vitamin retinyl palmitate following intramuscular administration
Authors: Hartmann D. , Gysel D. , Dubach U. C. , Forgo I.
Published: October 2006

Seven healthy male volunteers (21–24 y) received by the ventro‐gluteal route a single dose of 100 000 I.U. of the vitamin retinyl palmitate (RP) in a water‐miscible preparation (W) and 5 weeks later the same dose in an oily solution (S). After administration of W median (range) peak plasma concentrations of 5.6(4.4–8.7). 103 μg 1‐−1 were reached after 12 h and high levels persisted for another 50 h. At 144 h levels were still, by a factor 3, higher than baseline. Plasma levels of RP after S remained close to baseline (20–50 μg.1−1) suggesting negligibly low bioavailability. The plasma level profile of RP after W could well be described by use of a one‐compartment model with Weibull‐type absorption and Michaelis‐Menten elimination. The median (range) absolute bioavailability (estimates of lower limits) was 42 (32–52) per cent.
Effect of food on the bioavailability of adinazolam from a sustained release formulation: Effect of meal timing and lack of dose dumping
Authors: Fleishaker J. C. , Phillips J. P. , Lau H. S. H.
Published: October 2006

Food effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets. 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N‐desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state: no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0·5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.
Pharmacokinetics of dibenzylamine administered in a sustained drug delivery system with cefazolin
Authors: Calvo M. B. , Pedraz J. L. , Dominguez‐Gil A.
Published: October 2006

The pharmacokinetics of dibenzylamine administered in a sustained drug delivery system with cefazolin was studied after i.m. administration of a dose of 1250 mg to healthy volunteers. The serum and urine levels of dibenzylamine were determined by a GLC technique using a specific nitrogen‐phosphorus detector. Characterization of the kinetic parameters was performed by applying compartmental and non‐compartmental analysis.

Dibenzylamine was found to reach concentrations close to 300ng ml−1 approximately 5h after administration. The elimination constant had a value of 0·832 ± 0·821 h−1 (mean ± S.D.), which is higher than the release constant of the derivative (0·109 ± 0·072 h−1) (mean ± S.D.). These results show that release of dibenzylamine may be considered the limiting kinetic process, which governs the elimination of the product from the organism. Only a small amount of dibenzylamine is excreted in urine unchanged 3·43 ± 3·28 per cent (mean ± S.D.).

Using the pharmacokinetic parameters calculated for dibenzylamine, a prediction has been made of the concentrations reached in a multiple dosage regimen after administration of a dose of 1250 mg every 24h. The accumulation factor was 1·09.
Regional pharmacokinetics III. Modelling methods
Authors: Upton Richard N. , Runciman William B. , Mather Laurence E.
Published: October 2006

Regional pharmacokinetics is the study of drug concentrations in specific regions of the body due to drug uptake and elution. Mathematical methods of interpreting regional pharmacokinetic data can vary greatly in their complexity depending on their intended use (i.e. to describe or predict), but must reinforce rather than replace experimental pharmacokinetics. ‘Black box’ analysis provides and empirical method for the study of complex pharmacokinetic systems using either statistical moment or linear systems analysis. However, these methods are only applicable to linear and time‐invariant systems, and ignore the large body of information concerning the physiological and physicochemical basis of regional pharmacokinetics. Clearance concepts are suitable for describing linear drug uptake processes, but mass balance principles have wider applications in describing the rate and extent of both drug uptake and elution. Compartmental models of a region can vary from single compartment descriptions based on the concept of venous equilibrium to complex multi‐compartmental models of the intra‐vascular, interstitial, and intracellular spaces, in which drug transport between compartments is a function of drug binding and ionization. Ultimately, as more regional pharmacokinetic information is obtained, more complex three dimensional models may be necessary such as those used to describe the uptake of oxygen from capillaries.
Effect of H2‐receptor antagonists on the pharmacokinetics of 5‐fluorouracil in the rat and monkey
Authors: Dilloway Mark R. , Lant F.
Published: October 2006

The effect of short term (7 days) and long term (28 days) pretreatment with the imidazole H2‐receptor antagonist, cimetidine (CMT), on the pharmacokinetics of 5‐fluorouracil (5‐FUra) has been studied in the rat and cynomolgus monkey. Short‐term pretreatment of rats with CMT significantly increased t1/2,z by 29 per cent and AUC by 40 per cent: total body clearance was decreased by 30 per cent. Long‐term pretreatment exaggerated these effects. By contrast, short‐ and long‐term pretreatment with the furan H2‐receptor antagonist, ranitidine, caused no significant effect on 5‐FUra kinetics. In the monkey, 7 days pretreatment with CMT increased t1/2,z by 32 per cent leaving other 5‐FUra kinetic parameters unchanged; 28 days pretreatment increased both t1/2,z by 41 per cent and AUC by 100 per cent with a decrease in total body clearance of 5‐FUra of 48 per cent. CMT, but not RNT, inhibited cytosolic dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5‐FUra catabolism. It is proposed that the observed effects of CMT on 5‐FUra kinetics are the result of inhibition of DPD. This interaction has the potential for increasing systemic drug toxicity and it is therefore advisable that where H2‐receptor blockade is administered concurrently with 5‐FUra that a non‐imidazole based H2‐receptor antagonist such as RNT should be substituted for CMT.
A high‐performance liquid chromatographic method for the determination of stobadin pharmacokinetics in serum
Authors: Šoltés Ladislav , Kállay Zoltán , Bezek Štefan , Fedelesǒvá Viera
Published: October 2006

A high‐performance liquid chromatographic method was developed to determine stobadin pharmacokinetics in dog and man. The relative bioavailability of stobadin dipalmitate compared with dihydrochloride was 46·4 per cent in dog. In man peak serum concentrations ranged from 12 to 289ng ml−1 after a single oral dose of stobadin dipalmitate (0·79 to 2·5mg kg−1).
The influence of diuretics on the excretion and metabolism of doping agents: Part VI. Pseudoephedrine
Authors: Delbeke F. T. , Debackere M.
Published: October 2006

A capillary gas chromatographic method with nitrogen specific detection is presented for measuring pseudoephedrine and its major metabolite norpseudoephedrine in urine after derivatization with trifluoroacetic anhydride. After the oral intake of 49·2 mg pseudoephedrine (ACTIFED®) the active substance is nearly quantitatively excreted in urine over a 48 hr period. From 1 to 7 per cent is metabolized to norpseudoephedrine. The intake of acetazolamide results in a suppression of the pseudoephedrine concentration for at least 12h. The diuretic effect after the intake of 1·51 mineral water could be compared with the effect obtained with 1 mg bumetanide and results in a decrease in pseudoephedrine concentration by a factor 4 for several hours.
Etretinate absorption in the in situ perfused intestinal lumen: Preliminary studies in the rat
Authors: Zimmerman Cheryl L. , Johnson Kenneth E.
Published: October 2006

The absorption characteristics of etretinate were examined in the Sprague‐Dawley rat with the use of the in situ intestinal lumen perfusion model. Intestinal segments of 15–50cm were cannulated and perfused with etretinate solutions of 178–1405 μgml−1 in a single‐pass manner at flow rates of 0·15–0·96 ml min−1. The intestinal effluent was collected and analyzed by HPLC for etretinate, as was blood that was drawn from the jugular vein. Despite its lipophilic nature, etretinate does not appear to be well absorbed from the rat intestine; the maximum fraction disappearing from the intestinal lumen was approximately 0·35. The absorption of etretinate appeared to be controlled by the aqueous diffusion layer. There was no evidence that the uptake of etretinate by the gastrointestinal membrane involved an active transport system.
Drug redistribution and mean transit time concepts for nonlinear pharmacokinetic systems
Authors: Cheng Haiyung , Jusko William J.
Published: October 2006

Equations for the mean number of cycles through the peripheral system (R) and the mean transit time through the central compartment (MTTc) are derived for intravenous drugs with linear distribution and linear or nonlinear central elimination. This R is a function of distribution clearance (CLD), dose, and area under the plasma concentration–time curve (AUC). The MTTc is a function of the central volume of distribution, CLD, dose, and AUC. The application of the proposed calculations of R and MTTc was illustrated by computer simulations.
Pharmacokinetics of intravenous diltiazem and five of its metabolites in patients with chronic renal failure and in healthy volunteers
Authors: Tawashi Maha , Marc‐aurèle Julien , Bichet Daniel , Spénard Jean , Larivière Lyne , Plante Daniel , Caillé Gilles
Published: October 2006

The pharmacokinetics of diltiazem were studied in seven patients with chronic renal failure (CRF) not requiring dialysis and in three healthy volunteers after a rapid i.v. infusion of 20mg. Mean plasma concentrations at the end of infusion were 3·15 times higher in patients with CRF than in healthy volunteers. From 0·5 to 12h post‐infusion, the difference remained between 25 per cent and 73 per cent. Mean AUC0–∞ was statistically greater in patients than in volunteers while mean V area, CLtot, and CLren were statistically lower. The t1/2α and tβ values were not significantly (p > 0·05) different between patients and volunteers. Renal excretion was statistically more important in volunteers (6·6 per cent of the dose) than in patients (1·2 per cent of the dose). We therefore conclude that CRF does not influence t1/2β of diltiazem but it interferes with the extent and possibly the rate of its extravascular distribution. That could result in transient high plasma concentrations after rapid i.v. infusion.
Evaluation of controlled release formulations: Estimation of the duration of the zero‐order absorption and ascertainment of absorption kinetics
Authors: Macheras Panayotis
Published: October 2006

A compartmental approach for estimating the duration of the zero‐order absorption was developed. For drugs obeying one‐compartment model disposition, the estimation is based on an explicit relationship while an iterative process is required for drugs represented by two‐compartment kinetics. A method based on a double graphical plot for ascertaining absorption kinetics for drugs exhibiting one‐compartment model disposition was also developed.
In vitro and in vivo assessment of the bioavailability of potassium from a potassium tartrate tablet
Authors: Whiting Susan J. , Gorecki Dennis K. J. , Jones Dennis
Published: October 2006

The bioavailability of potassium from orally administered potassium tartrate was evaluated in 20 normal subjects under metabolic balance conditions. Subjects were given 34 mmol potassium (5 tablets of Cal‐K®) as a divided dose on each of 2 consecutive days. Urinary excretion of potassium, as determined from 24‐h urinary collections on the 3 days preceding dosage totalled 192·6 ± 50·9 mmol (mean ± S.D., n = 20). It increased significantly (p < 0·05) to 258·7 ± 54·2 mmol for the 2 days of dosage and the following day. The difference of 66.1 mmol representing absorbed potassium was close to the 68 mmol potassium given and indicated a bioavailability of potassium in excess of 97 per cent; after correction for creatinine excretion, potassium recovery rose to 99·9 per cent. The dissolution characteristics of the Cal‐K® tablets were also determined. After dissolution in simulated gastric juice (pH 1·2), 84·4 ± 10·6 per cent (mean ± S.D., 6 experiments) was dissolved; after adjustment to pH 7·3, dissolved potassium increased to 91·3·8·5 per cent. No precipitation or residue formed as a result of the pH change. Both sets of results indicate that potassium from these potassium tartrate tablets is in a highly bioavailable form.
Pharmacokinetic studies of the nitroglycerin metabolites, 1,2‐ and 1,3‐ glyceryl dinitrates, in the rat
Authors: Lau David T.‐W. , Gumbleton Mark , Labisch Christoph , Benet Leslie Z.
Published: October 2006

1,2‐ and 1,3‐glyceryl dinitrates (1,2‐GDN and 1,3‐GDN) are the primary metabolites of glyceryl trinitrate, a commonly used anti‐anginal agent. The goal of this study was to examine the pharmacokinetic properties of these metabolites in rats. Sprague‐Dawley rats were infused intravenously with 0·25 or 2·0 μgmin−1 of either 1,2‐ or 1,3‐GDN for 70 min, during which steady state blood concentrations were achieved. Post‐infusion blood samples were collected for 30 min. 1,2‐GDN was found to possess slightly higher clearance (32·3 vs 21·8 ml min−1 kg−1) and volume of distribution (695 vs 454 ml kg−1) than 1,3‐GDN; however, the two metabolites exhibited similar mean residence times (22·0 vs 21·8 min). Upon an 8‐fold increase in the infusion rate, the pharmacokinetic parameters were not significantly altered for either 1,2‐ or 1,3‐GDN. When each GDN was co‐infused with an 8‐fold higher dose of the other GDN, there were also no significant changes in the parameters.