bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI‐6, in rhesus monkeys (Macaca mulatta): Effect of atropine, diazepam, and methoxyflurane anesthesia
Authors: Clement John G. , Lee Mary J. , Simons Keith J. , Briggs Colin J. 
Published: October 2006

AbstractThe pharmacokinetics of the bispyridinium oxime HI‐6 (CAS reg. no. 34433–31–3;l‐(((4‐aminocarbonyl)pyridinio)methoxyl)methyI)‐2‐((hydroxyimino)methyl)‐pyridinium dichloride was investigated in rhesus monkeys (Macaca mulatta). The effects of methoxyflurane anesthesia, administration of atropine with and without diazepam were determined on the serum half‐life (t1/2), clearance rate (CL), and the volume of distribution (Vd) following intramuscular (IM) administration of HI‐6 (30 mg kg−1). The control t1/2, CL and Vd of HI‐6 were 27 min, 8–6 ml min−1 kg−1 and 0.34 I kg−1, respectively. These parameters were unaffected by the co‐administration of either atropine (0.5 mg kg−1, IM) or atropine and diazepam (0.5 mg kg−1, IM+0.2 mg kg−1 IV, respectively). Methoxyflurane anesthesia resulted in a significant increase in the HI‐6 t1/2 to 61 min concomitant with a decrease in the CL to 4.1 ml min−1 kg−1 with no change in the Vd. The increase in the t1/2 of HI‐6 in methoxyflurane anesthetized monkeys is probably the result of a decrease in the clearance rate and, thus, excretion of HI‐6 by the kidneys.
Pharmacokinetics of morphine and its surrogates X: Analyses and pharmacokinetics of buprenorphine in dogs
Authors: Garrett Edward R. , Chandran V. Ravi 
Published: October 2006

AbstractSpecific and sensitive reverse‐phase HPLC assays of buprenorphine and its metabolite in biological fluids were developed with sensitivities of 2–6 ngml−1 using fluorimetric detection. Pharmacokinetics were monitored on acute bolus administration of buprenorphine in 6 dogs within the 0.7–2.6 mg kg−1 dose range. Toxicity was circumvented when terminal plasma concentrations were increased by infusing 3.7–4.8mg kg−1 doses of buprenorphine over 3 h in six studies in 6 dogs. The terminal rate constants of the IV infusion studies from the triexponential fits of plasma concentration–time data averaged 41.6 ± 7.5 h with an averaged total body clearance of 191 ± 19ml min−1. This terminal rate constant was in contrast to the < 100 min half‐life of the second exponential fitting of the less lipophilic morphine, naloxone, and naltrexone. The apparent volumes of distribution of buprenorphine, referenced to the total plasma concentration, were 33 ± 6 1 (Vc, central compartment volume) and 663 ± 891 (Vd, total body volume), indicative of a highly bound, sequestered or lipophilic drug. Unchanged buprenorphine was insignificantly renally (<0.2 per cent of the dose) and biliary (<0.6 per cent) excreted. The major route of buprenorphine disposition was by hepatic conjugation to glucuronide which was eliminated into the bile (about 92 per cent) with only small amounts appearing in urine (< 1 per cent as metabolite). Minor metabolites excreted in the bile accounted for about 3 per cent of the administered dose. Direct IV administration of the metabolite, buprenorphine glucuronide, gave a terminal half‐life of 6 h and more than 90 per cent of the systemically circulating metabolite was excreted in bile; only 10 per cent in urine. The oral bioavailability, estimated from the areas under the buprenorphine plasma concentration–time curve following IV and oral administration of buprenorphine in the dogs, was 3–6 per cent. There were no apparent correlations of the buprenorphine time course with cardiovascular parameters such as heart rate, ECG, and blood pressure. Miotic effect was significant. Respiratory depression was observed during the first 4 h after IV bolus injection, but not during the infusion studies.
Species differences in the pharmacokinetics of recainam, a new anti‐arrhythmic drug
Authors: Scatina J. A. , Kimmel H. B. , Weinstein V. , Troy S. M. , Sisenwine S. F. , Cayen M. N. 
Published: October 2006

AbstractThe pharmacokinetics of recainam, an anti‐arrhythmic drug, were compared in mice, rats, rabbits, dogs, rhesus monkeys, and man, Bioavailability was virtually complete in monkeys and dogs, 67 per cent in man and 51 per cent in rats. Non‐linear kinetics between the oral and i.v. dose in rabbits precluded estimation of bioavailability. Linear plasma dose proportionality occurred in dogs between 6 and 60 mgkg−1 oral doses and rhesus monkeys between 1 and 15 mgkg−1 i.v. doses. A greater than proportional increase in the plasma AUC of recainam occurred between oral doses ranging from 54–208 mg kg−1 in mice, 25–110 mg kg−1 in rats, and 50–100 mg kg−1 in rabbits. In human subjects, the AUC/unit dose was linear between 400 and 800 mg. The terminal elimination t1/2 of recainam ranged from 1–5 h in laboratory animals and man. The plasma Cmax and AUC of recainam were virtually identical after single or multiple (21 day) oral doses in dogs. After an i.v. dose, plasma clearance of recainam (1 kg−1. h) was 4·9–5·2 in rats and rabbits and 0·4–1·9 in dogs, rhesus monkeys, and man. The steady state volume of distribution was 2–5 times larger than the total body water of laboratory animals and man. Recainam was very poorly bound (10–45 per cent) to the serum proteins of rodents, rabbits, dogs, rhesus monkeys and man. In rhesus monkeys and man, recainam accounted for 10 per cent and 70 per cent, respectively, of the plasma radioactivity at 6h post‐dose. The pharmacokinetic profile of recainam in dogs most closely resembled that of man.
Microbially controlled drug delivery to the colon
Authors: Rubinstein Abraham 
Published: October 2006

AbstractThe human gastrointestinal tract consists of a highly complex ecosystem of aerobic and anaerobic microorganisms that plays a significant role in the metabolism of nutrients as well as drugs. In the colon, bacteria ferment various types of substrates that are not susceptible to digestion in the small intestine. This arouses interest in specific drugs, drug delivery systems, and prodrugs that escape small bowel digestion, arrive intact, and are absorbed or degraded in the large bowel. For the past forty years, experience has been gained with the azo prodrug of 5‐amino salicylic acid, salazopyrine, which is cleaved by colonic bacteria to its parent drug. Some laxative drugs were also reported to degrade into active metabolites in the colon. Lately equally interesting and more sophisticated microbial controlled delivery systems, have been developed based on similar principles.
Oxidative versus conjugative biotransformation of temazepam
Authors: Locniskar Ann , Greenblatt David J. 
Published: October 2006

AbstractTwenty‐four healthy volunteers, aged 21–59 years, received single 30 mg oral doses of the benzodiazepine hypnotic temazepam. Levels of intact temazepam were determined in multiple plasma samples drawn during 48 h after dosage. Intact temazepam, its direct glucuronide conjugate, and the conjugate of its demethylated (oxidized) metabolite oxazepam were measured in two consecutive 24‐h urine collections. Mean kinetic variables for temazepam in plasma were: peak plasma level (Cmax), 873 ng ml−1; time of peak, 1·36 h after dosage; volume of distribution, 0·961 kg−1; elimination half‐life, 9·9 h; clearance, 1·16 ml min−1 kg−1. Volume of distribution increased significantly with body weight (r = 0·67, p < 0·001), and Cmax decreased with weight (r = −0·58, p < 0·01). Only 0·2 per cent of the dose was excreted as intact temazepam, and negligible amounts as intact oxazepam. However, 39 per cent of the dose was recovered as temazepam glucuronide, and oxazepam glucuronide accounted for another 4·7 per cent of the dose. The remainder was not accounted for. Thus, a significant fraction of temazepam clearance occurs by direct glucuronide conjugation, with the conjugate temazepam glucuronide excreted in urine. A much smaller fraction undergoes parallel oxidation to form oxazepam, which is subsequently conjugated to oxazepam glucuronide and excreted in urine.
The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen in humans
Authors: Evans Allan M. , Nation Roger L. , Sansom Lloyd N. , Bochner Felix , Somogyi Andrew A. 
Published: October 2006

AbstractIbuprofen is a chiral drug which is used clinically as a racemate. The pharmacological properties of ibuprofen reside almost exclusively with the S(+)‐enantiomer. However, a portion of R(−)‐ibuprofen is metabolically inverted to its pharmacologically active, mirror‐image form. To investigate the influence of increasing dose of racemic ibuprofen on the pharmacokinetics of its individual enantiomers, four healthy male volunteers were given racemic ibuprofen (200, 400, 800, and 1200 mg), orally, on four occasions. The study was conducted using a balanced cross‐over design. The extent of absorption of ibuprofen, as assessed by the total urinary recovery of ibuprofen and its metabolites, was extensive and independent of the administered dose. At all four doses, the area under the total and unbound plasma concentration‐time curves (AUC and AUCu, respectively), and the unbound fraction in plasma, were significantly greater for the S(+)‐enantiomer.With increasing ibuprofen dose, there was a less than proportional increase in the AUC of each enantiomer, while the AUCu for both enantiomers increased in direct proportion to the administered dose. The time‐averaged unbound fraction of each enantiomer increased significantly with increasing dose, which caused the non‐linearity between AUC and dose. It was predicted that the metabolic intrinsic clearance of each enantiomer, and the fraction of R(−)‐ibuprofen which was metabolically inverted to S(+)‐ibuprofen, was independent of the administered dose.
Pharmacokinetics of aditoprim in goats using a radioassay
Authors: Iqbal M. Perwaiz , Mahboobali N. , Niazi Sarfaraz K. , Mahmood M. Anwar 
Published: October 2006

AbstractA simple, highly sensitive radioassay was developed for the activity of a newly discovered inhibitor of dihydrofolate reductase (DHFR), aditoprim. The procedure is based on the inhibition of binding of [3H]‐methotrexate ([3H]MTX) with bacterial dihydrofolate reductase by the antifolate, aditoprim. The analytic sensitivity using this binding inhibition method was less than 5 ng in plasma. The procedure developed requires no extraction of the drug from the plasma. The variation of simultaneous duplicate determinations was 6·3 per cent, whereas the variability of plasma samples assayed on different days was less than 11 per cent. The assay developed was applied to study the pharmacokinetics of aditoprim in the goat. In comparison with trimethoprim (TMP), the new inhibitor of DHFR, aditoprim, had a longer half‐life and a larger volume of distribution, suggesting enhanced and prolonged antibacterial activity of aditoprim over TMP.
Pharmacokinetics and safety of single oral doses of lomefloxacin
Authors: Morse Irwin S. 
Published: October 2006

AbstractThe pharmacokinetics of 100mg, 200 mg, 400 mg, 600 mg, and 800 mg of lomefloxacin, a quinolone antimicrobial, were examined in a single sequential rising dose, placebocontrolled, crossover study. Each of 30 healthy male subjects (6 per group) received placebo and one dose of lomefloxacin, separated by 5 days.Test results (physical examinations, laboratory and hematology panels, vital signs, neurological and ophthalmological examinations, EEG or urinalysis) revealed no clinically significant differences compared to baseline.Mean Cmax values (0·92 μg ml−1) increased linearly with dose. Mean Jmax averaged 1·13 ± 0·5 h and mean t1/2, 7·8 ± 1·0 h over all doses. There was a small influence of dose on the AUC0‐048.Mean urinary concentrations during the first 4 h postdosing ranged from 79 to 454 μ ml−1 Urine concentrations remained ≦ 15 μg ml−1 over 24 h at the lowest dose. Maximum urinary excretion rate, Rmax, ranged from 5·84 mg h−1 to 34·90 mg h−1. Dose normalized Rmax and XU96 (per cent of dose) were unaffected by dose. Mean renal clearance decreased at higher doses.In conclusion, lomefloxacin was well tolerated in doses up to 800 mg. Lomefloxacin is rapidly absorbed with an elimination half‐life of approximately 8 h. The data suggest that the drug can be effectively administered once daily.
Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs
Authors: Schmitt M. , Guentert T. W. 
Published: October 2006

AbstractAbsorption and disposition characteristics of carprofen were compared in the dog after intravenous, oral, and rectal administrations. Rectal formulations included an aqueous solution and a suppository. Single doses of 100mg carprofen were given in a cross‐over design and plasma concentrations of unchanged drug were determined by HPLC. Plasma concentration–time profiles could be adequately described after intravenous and extravascular administrations by tri‐and biexponential functions, respectively. After intravenous applications the basic disposition parameters could be determined: mean (±S.D.) elimination half‐life was about 11·7 (±3·1)h; volume of distribution ranged from 0·12 to 0·221kg−1 and total plasma clearance was about 0·017 ± 0·003 1 h kg−1. After oral dosing, carprofen was rapidly absorbed (time of maximum concentration: 0·83 ± 0·61 h) and comparison with the intravenous solution indicated complete bioavailability. After rectal administration, the rate of absorption evaluated through tmax and calculation of mean absorption times was always slower than after oral dosing. Relative bioavailabilities of the drug from the suppository were about 20 per cent lower than from rectal solutions. No significant difference in rates of absorption of carprofen from rectal solution and suppository was seen; this allowed the conclusion that drug release from the semi‐solid dosage form was not the rate‐limiting step in carprofen absorption from the suppository. From the present study, it is concluded that rectal administration of carprofen offers an alternative to the oral route of drug intake.
Dextran sulfate disposition in the rat
Authors: Foster B. C. , Gallicano K. D. , Whitehouse L. W. , McGilveray I. J. , Khan S. R. 
Published: October 2006

AbstractComparative studies of oral and intravenous administration of tritiated dextran sulfate in rats showed markedly different distribution patterns. Following IV dosing about 50 per cent of the radioactivity was recovered in feces and urine within 24 h. The major portion of the recoverable dose was eliminated in the urine as dextran sulfate within 3 h after administration. In orally treated rats only about 32 per cent of the 3H was recovered in the feces and urine, the major fraction being associated with unabsorbed dextran sulfate in the feces. The remainder of the dose in both treatment groups has apparently distributed throughout the rat body with some accumulation in the liver, kidney and spleen. Consequently, the disposition of about 67 per cent or the oral dose could not be fully accounted for by these excretion routes. However, separation with Sephadex columns showed similarities in the 24 h plasma and urine profiles of the IV and orally dosed rats which suggest that while the oral dose was absorbed as dextran sulfate, it underwent rapid metabolism to small molecular weight products prior to entering the systemic circulation which were then widely distributed within the rat.
The influence of hepatic cirrhosis on the pharmacokinetics of benazepril hydrochloride
Authors: Kaiser G. , Ackermann R. , Gschwind H. P. , James I. M. , Sprengers D. , McIntyre N. , Defalco A. , Holmes I. B. 
Published: October 2006

AbstractThe influence of hepatic disease on the pharmacokinetics of the new ACE inhibitor, benazepril hydrochloride, was evaluated in 12 male patients suffering from liver cirrhosis. The patients received a single oral 20 mg dose. The plasma concentrations and urinary excretion of unchanged benazepril and its active metabolite benazeprilat were determined. Compared with a historical control group of healthy volunteers treated with the same benazepril. HCl dose, the plasma concentrations of benazepril were doubled in the cirrhotic patients. However, the time to reach maximum concentration (0·5 h) was not affected. The plasma kinetics and the urinary excretion of the metabolite benazeprilat were not significantly altered: Area under the curve and maximum concentration as well as time to maximum concentration (1·5 h) were comparable with those in the healthy subjects. There was also no significant difference between the two populations for the total urinary excretion and the renal clearance of benazeprilat. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 94 per cent, respectively). In conclusion, the rate and the amount of bioactivation of the inactive prodrug benazepril to the active benazeprilat were virtually unaffected by hepatic cirrhosis. Thus, there seems to be no need for dosage adjustment of benazepril hydrochloride in patients suffering from cirrhosis of the liver.
Pharmacokinetics of sulfamethoxazole and trimethoprim in mexicans: Bioequivalence of two oral formulations (URO‐TS D® and bactrim F®)
Authors: Flores‐Murrieta F. J. , Castañgeda‐Hernández G. , Menéndez J. C. , Chávez F. , Herrera J. E. , Hong E. 
Published: October 2006

AbstractTwo oral pharmaceutical formulations (URO‐TS D® and Bactrim F®) containing 800 mg of sulfamethoxazole (SMZ) and 160 mg of trimethoprim (TMP) were given to 10 Mexican healthy volunteers, following a randomized cross‐over design. Blood and urine samples were obtained, concentrations of TMP, SMZ, and its metabolite N4‐acetyl SMZ were measured by HPLC and pharmacokinetic analyses were performed. The observed Cmax' tmax' half‐life, AUC, and cumulative urinary excretion values for the three compounds studied were within the ranges that have been previously reported for European and North American subjects. Therefore, it appears that pharmacokinetics of SMZ and TMP in Mexicans are similar to those observed in Caucasian populations. When the two studied formulations were compared, no statistically significant differences were detected in any pharmacokinetic parameter. Therefore, it is concluded that both brands tested are bioequivalent. Moreover, these two formulations manufactured in Mexico yield SMZ and TMP plasma and urine levels similar to those obtained with equivalent formulations of European or North American origin.
Disposition of phenytoin in analbuminemic rats
Authors: Hirate Junji , Horikoshi Isamu , Nagase Sumi 
Published: October 2006

AbstractThe disposition characteristics of phenytoin were investigated in analbuminemic rats to study the effect of plasma protein binding on phenytoin disposition. Blood and plasma phenytoin concentration determinations, measurement of plasma protein phenytoin binding, and whole‐body autoradiography were performed after intravenous bolus injection of 10mg kg−1 of phenytoin. When plasma phenytoin was assayed, total body phenytoin clearance (CL) was faster and its apparent volume of distribution (Vd) greater in the analbuminemic rats in comparison to the controls. The plasma protein binding of phenytoin was significantly lower in the analbuminemic rats, suggesting the disposition characteristics of phenytoin were altered in the presence of low plasma albumin concentrations due to reduced plasma phenytoin protein binding. On the other hand, when blood phenytoin levels were analyzed, no difference in CL and a less pronounced difference in Vd were noted between the two groups of rats. The red blood cell‐to‐plasma phenytoin concentration ratios were greater in analbuminemic rats, suggesting that the distribution of phenytoin into red blood cells was greater in the mutant rats.
Pharmacokinetics of urinary metabolites of cannabidiol in the dog
Authors: Samara Emil , Bialer Meir , Harvey David J. 
Published: October 2006

AbstractThe pharmacokinetics of cannabidiol (CBD) and six of its urinary metabolites was investigated in dogs. CBD was administered intravenously to three dogs, and urine was collected at specified time intervals over a period of 30h. The apparent terminal half‐life of CBD calculated from the slope of the sigma minus plot was significantly shorter (2h) than the half‐life of CBD calculated from plasma data (8h), and the apparent terminal half‐life of the metabolites was similar to that of the CBD calculated from plasma data, indicating that the elimination of these metabolites was formation rate limited.The time course of the metabolite excretion could be divided into two phases: the first phase contained mainly monohydroxy metabolites, and the second phase contained mainly metabolites with a carboxylic acid moiety in their side‐chain.
Absorption of a pharmacological dose of vitamin D3 from two different lipid vehicles in man: Comparison of peanut oil and a medium chain triglyceride
Authors: Holmberg Inger , Aksnes Lage , Berlin Tomas , Lindbäck Bengt , Zemgals Justine , Lindeke Björn 
Published: October 2006

AbstractThe absorption of a pharmacological dose of vitamin D3 from two different lipid vehicles, peanut oil, containing long chain fatty acids, and a medium chain triglyceride was compared. Serial measurements of the serum concentration of vitamin D3 after dosage were made. The serum levels of 25‐hydroxyvitamin D3, the major circulating vitamin D3 metabolite, were also determined. The analytical methods used were based on HPLC. In the fasting state, the serum levels of vitamin D3 were significantly higher after administration in peanut oil than after administration in the medium chain triglyceride. When the vitamin D3 dose was ingested together with food no difference between the two formulations was observed. Only small inter‐formulation differences in serum 25‐hydroxyvitamin D3 levels were detected. The results indicate that the presence of long chain fatty acids facilitates the absorption of vitamin D3.
A study of the pharmacokinetics and pharmacodynamics of nifedipine in combination with atenolol
Authors: Fitzsimons T. J. , Norris S. C. , Adam H. K. , Ryan J. , McAinsh J. 
Published: October 2006

AbstractThis double‐blind randomized, crossover study was undertaken to determine the pharmacokinetic properties of nifedipine retard and atenolol when given separately, as a free or a fixed combination, compared with placebo in 15 healthy male volunteers. There was no difference between the three atenolol formulations in time to maximum blood concentration or elimination half‐life. The fixed combination showed significant differences in both maximum observed blood concentrations (+16 per cent) and total area under the curve (+16 per cent) compared to atenolol alone. Urinary recovery of unchanged drug from the fixed combination was also slightly increased but the difference was not statistically significant. Furthermore, statistical evaluation of the plasma pharmacokinetics of nifedipine retard and urinary recovery of nifedipine metabolite showed that all three formulations were indistinguishable. Thus, it is concluded that the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and that the bioavailability of both drugs in the fixed combination is equivalent to that of the single entities.
Pharmacokinetics of oral diltiazem and five of its metabolites in patients with chronic renal failure
Authors: Tawashi Maha , Marc‐aurèle Julien , Bichet Daniel , Spénard Jean , Larivière Lyne , Plante Daniel , Caillé Gilles 
Published: October 2006

AbstractThe pharmacokinetics of oral diltiazem were studied in 10 patients with chronic renal failure not requiring dialysis and in five healthy volunteers after a single dose of 120mg. We found that patients with chronic renal failure had lower amounts of unchanged diltiazem and of its main metabolite (MA) in urine and a trend to have slightly higher values of plasma concentration. Since the terminal elimination phase is not affected by chronic renal failure we conclude that this trend is probably the result of alterations in the volume of distribution of diltiazem in these patients.