bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic analysis of absorption and metabolism of dopamine and a dopamine prodrug in dogs
Authors: Murata Kazuo , Noda Kazuo , Kohno Keiichi , Samejima Masayoshi
Published: October 2006

Pharmacokinetic compartment models were constructed to describe the absorption and metabolism of dopamine (DA) and DA prodrug, N‐(N‐acetyl‐L‐methionyl)0,0‐bis(ethoxycarbonyl) dopamine(1). Plasma concentrations of DA, DA‐SO4. and DOPAC after oral administration of DA to dogs, were analysed using the pharmacokinetic model assuming the contribution of first‐pass metabolism for the formation of DA‐SO4 and DOPAC, Though plasma concentration of DA was quite different from that of DA‐SO4 or DOPAC, these data were simultaneously analysed with a good fitting curve. The apparent absorption rate constant of DA(K1) was proved to be much smaller than the apparent formation rate constants of DA‐SO4(K2) or DOPAC(K3). It was found that the compartment model is useful for the evaluation of absorption and metabolic inactivation of DA. Plasma concentration of DA, N‐(N‐acetyl‐L‐methionyl)dopamine(2), DA‐SO4, and DOPAC after oral administration of 1 were simultaneously analysed using the compartment model including the first‐pass metabolism and two‐fraction dissolution process. Good fitting curves were obtained. The apparent formation rate constant of 2(K4) is larger than that of DA‐SO4(K5) or DOPAC(K6); thus it was shown that two protective groups of 1 reduced the metabolism of DA and 2 specially played an important role to the reduction of first‐pass metabolism. From these results, it was found to be possible to give a pharmacokinetic interpretation for the mechanism of reduction of first‐pass metabolism of DA.
Effect of nifedipine on antipyrine and theophylline disposition
Authors: Adebayo G. I. , Mabadeje A. F. B.
Published: October 2006

On the basis of reports that some calcium channel blockers impair the elimination of some drugs, the effect of nifedipine on the disposition of antipyrine and theophylline was assessed in healthy volunteers. Antipyrine half‐life of 10·04 ± 1·43 h (mean ± SD) after a week intake of nifedipine (20 mg twice daily) was not significantly different from the control value of 10·64 ± 2·15 h; nor was that of 10·02 ± 1·49 h after 2 weeks pretreatment with the calcium channel blocker in eight healthy volunteers. Control antipyrine clearance (ml min−1) of 44·40 ± 10·58 was not significantly different from that of 45·66 ± 9·34 and 46·87 ± 9·63 after nifedipine pretreatment of 1 and 2 weeks, respectively. Similarly volume of distribution was unaltered: 0·601 ± 0·074. 0·591 ± 0·078 and 0·602 ± 0·051 1 kg−1, respectively.

A week pretreatment with nifedipine did not significantly alter either of theophylline half‐life (7·32 ± 0·81 h (control) to 7·50 ± 0·80 h) or clearance (42·10 ± 5·84 ml min−1 (control) to 43·77 ± 4·00 ml min−1) in six volunteers. However the change in volume of distribution: 0·451 ± 0·053 1kg−1 (control) to 0·483 ± 0·0621 kg−1 was significant (p < 0·025). Generally, theophylline plasma levels were lower after nifedipine pretreatment and the difference was significant at 2 and 4 h post‐dosing (p < 0·05).

It is suggested that nifedipine, unlike diltiazem and verapamil, is unlikely to interfere with the functional integrity of the hepatic mixed‐function oxygenase enzymes, but might displace theophylline from plasma protein.
Bioavailability of a new sustained‐release theophylline capsule in fasted and non‐fasted healthy subjects: Single and multiple dosing studies
Authors: West Raelene J. , Boehm Garth , Dwyer Mark , Williams Desmond B. , Sansom Lloyd N. , Penna Antonio C.
Published: October 2006

Eighteen healthy, non‐smoking, adult volunteers participated in single and multiple dose three‐way crossover studies to evaluate a sustained‐release, pellet‐filled capsule of theophylline, Austyn. The effect of food on the bioavailability of the sustained‐release capsule was investigated by administering 300 mg single doses of Austyn, with a high‐fat meal and without food and a divided 300 mg dose of the reference product Elixophyllin(R) elixir, given after fasting. Plasma theophylline concentrations were measured by fluorescence polarization immunoassay (FPIA) which had been validated against HPLC. The single dose study data showed that there were no significant differences (n = 18, ANOVA, p > 0·05) between the three regimens with respect to AUC0−∞ values (mghl−1), (mean ± SD); Elixophyllin® fasting = 97·1 ± 33·7, Austy with food = 90·9 ± 31·3. Austyn fasting = 91·2 ± 33·8. Similarly, multiple dosing with rapid‐release Nuelin(r) tablets, Austyn capsules, and sustained‐release Theo‐Dur(r) tablets demonstrated that there were no significant differences between regimens with respect to AUC0‐24h, AUC0‐12h, and AUC12‐24h values calculated from the steady‐state concentrations (5th day, 24 h sampling). However, the percentage fluctuation at steady‐state over the total blood sampling period was significantly less for treatment with the sustained‐release capsule, Austyn, compared with the sustained‐release tablet, Theo‐Dur(r) (Austyn = 36·7 ± 13·7 per cent, Theo‐Dur® = 53·1 ± 14·1 per cent). The results of the single and multiple dose studies indicate that Austyn capsules demonstrate complete bioavailability, and good controlled release characteristics not influenced by concomitant intake of a high‐fat meal and with no eyidence of dose dumping.
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

The 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

Specific 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

The 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

The 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

Twenty‐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

Ibuprofen 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

A 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

The 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

Absorption 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

Comparative 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

The 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

Two 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

The 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

The 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

The 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

This 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

The 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.
Distribution of oral nimesulide in female genital tissues
Authors: Pulkkinen Martti O. , Vuento Maarit , Macciocchi Alberto , Monti Tlziana
Published: October 2006

Nimesulide is a non‐steroidal anti‐inflammatory agent which has proved to be effective in reducing menstrual discomfort in dysmenorrhoeaic women. To determine the concentrations of this drug in the uterus (fundus, cervix), oviduct, and ovaries and to correlate these findings with plasma concentrations, a single oral dose of 100mg nimesulide was administered 1 to 6h before surgery to 12 women undergoing hysterectomy and salpingo‐oophorectomy, mainly for fibroids. Tissue samples were taken, concentration of nimesulide measured by HPLC, and findings compared with plasma concentrations. One patient not undergoing treatment served as control. Nimesulide concentration in the tissues studied was highest 3h after administration, as expected from the drug's pharmacokinetic profile. The highest tissue/plasma ratio (0·5) was also found at that time. Average tissue concentrations at 1, 2, 3, and 6h after drug intake ranged from 0·3 to 1·8μgg−1, and plasma concentrations from 2·6 to 4·1μgml−1. Nimesulide was evenly distributed in the tissues studied.
Distribution kinetics of netilmicin in human blister fluid: Effect of renal impairment
Authors: Lanao J. M. , López A. , Domínguez‐gil A. , Martin J. , Gómez J. R. , Tabernero J. M.
Published: October 2006

The pharmacokinetics of netilmicin in plasma and blister fluid were compared in 10 healthy volunteers with normal renal function and 10 voluntary patients with varying degrees of renal impairment. Netilmicin kinetics in plasma were characterized by an open two‐compartment kinetic model. For the study of the kinetics of the antibiotic in blister fluid a specific kinetic distribution model was employed. In the healthy volunteers the plasma kinetics of netilmicin showed a behaviour similar to that of other aminoglycoside antibiotics, although a high blister/plasma partition coefficient was obtained, with a mean value of 4·27·1·65. The transfer of netilmicin in blister fluid governed by the constants Klb/Vb and Kbl had mean values of 0·19·0·09h−1 I−1 and 0·25·0·10h−1, respectively. In the patients with renal impairment plasma and blister fluid antibiotic levels showed a progressive accumulation. In these patients the affinity of netilmicin for blister fluid was significantly altered. The blister/plasma partition coefficient in this group of patients had a mean value of 2·65·1·33; the decrease being statistically significant (p=0·023) with respect to the value obtained in the healthy volunteers. Similarly, the exit constant of netilmicin from blister fluid (Kbl) showed a statistically significant increase (p=0·035) in the patients with renal impairment. The findings point to a loss of affinity of netilmicin for blister fluid as a result of renal impairment. Linear and logarithmic relationships were established between some pharmacokinetic parameters and creatinine clearance. Dosage schedules are proposed for netilmicin in patients with renal impairment.
Effects of ethanol and Δ9‐tetrahydrocannabinol on phencyclidine disposition in dogs
Authors: Godley Paul J. , Moore Emory S. , Woodworth James R. , Fineg Jerry
Published: October 2006

A three‐way crossover study was performed to determine the influence of Δ9‐tetrahydro‐cannabinol (THC) and ethanol (EtOH) separately upon phencyclidine (PCP) disposition in dogs. Seven dogs were given three single dose treatments: 1·5mg PCP kg−1 i.v., 1·5 mg PCP kg−1 i.v. with 0·4mgkg−1 THC i.v., and 1·5 mg PCP kg−1 i.v. with 1·25g EtOH kg−1 i.v. PCP was measured in plasma samples collected for 24h after administration of each treatment, with several pharmacokinetic parameters calculated from the plasma concentration vs time data. The PCP serum Cls values were significantly lower when administered with THC than when administered alone, with no significant change in Vβ or t1/2. EtOH did not induce significant changes in any PCP pharmacokinetic parameter, although mean Cls and Vβ were increased. These results confirm the observed THC inhibition of PCP metabolism, and suggest that the enhanced pharmacologic action of PCP by THC may result from higher serum PCP concentrations. These results further suggest that enhanced PCP actions by acute EtOH administration may result from increased PCP distribution to the CNS.
Characterization of ethiofos absorption in the rat small intestine
Authors: Geary Richard S. , Swynnerton Nollie F. , Timmons Scott F. , Mangold Donald J.
Published: October 2006

The absorption characteristics of ethiofos were studied using the rat in situ intestine circulating perfusion technique. Slow absorption kinetics were observed for ethiofos with varying rates of absorption and metabolism/degradation in situ as a function of buffer and absorption enhancers. In most cases less than 10 per cent of the radiolabeled compound is lost from the circulating perfusate in 90 min. In addition, over the same time period greater than 40 per cent of the intact parent compound was lost by degradation. Much of the difference can be accounted for in the formation of the free thiol metabolite, WR‐1065, suggesting ester hydrolysis or metabolic activity. Good stability was observed in all perfusate systems ex vivo indicating that the degradation occurs in situ. The disodium salt of ethylenediaminetetraacetic acid (EDTA) was shown to be an effective absorption enhancer of ethiofos. The enhancement of intestinal absorption by EDTA was dose‐dependent resulting in a 20‐fold increase in blood levels of ethiofos in the portal blood. Follow‐up studies in the rhesus monkey confirm this observation. Salicylate and dimethylsulfoxide (DMSO) also resulted in absorption enhancement although to a lesser degree than that seen after EDTA treatment. Addition of several alkaline phosphatase inhibitors did not significantly improve absorption of ethiofos in the rat small intestine. Proposed mechanism(s) for intestinal absorption and absorption enhancement of ethiofos are discussed.
Characterization of WR‐1065 absorption in the rat small intestine
Authors: Geary R. S. , Swynnerton N. F. , Timmons S. F. , Mangold D. J.
Published: October 2006

A circulating in situ rat small intestine absorption model was used to study the lumenal metabolism and absorption of [14]WR‐1065. WR‐1065 was found to be more tissue reactive and toxic than its phosphorylated form, ethiofos, at equimolar perfusate concentrations. The disappearance profiles of the radiolabeled drug and free WR‐1065 indicate that WR‐1065 is extensively metabolized in the intestinal lumen prior to absorption. Coadministration of disodium ethylenediaminetetraacetic acid enhances the absorption of the free thiol although not to the same extent as seen with ethiofos. Perfusion of WR‐1065 in citrate buffer decreased lumenal degradation of the drug but resulted in decreased absorption. The total material converted to WR‐1065 portal blood profiles following ethiofos and WR‐1065 perfusion were altered possibly due to distribution and metabolism differences. This study coupled with earlier work completed on ethiofos have increased our understanding of the significant barriers to absorption observed following oral administration of these compounds.
Apparent stereoselectivity in propafenone uptake by human and rat erythrocytes
Authors: Mehvar Reza
Published: October 2006

The distribution of propafenone (PPF) enantiomers between the plasma and red blood cells (RBCs) was investigated using human and rat blood. In separate experiments, effects of incubation time (15–60 min), blood concentration (100–5000 ng ml−1), and plasma proteins on the RBC uptake of the enantiomers were studied. In both humans and rats, the distribution of propafenone enantiomers into RBCs was rapid, extensive, and stereoselective. However, the extent of RBC uptake and the direction of stereoselectivity were different in these two species. In humans, preferential distribution of (–)‐PPF into RBCs resulted in lower plasma concentrations for this enantiomer, whereas in rat plasma, (–)‐PPF was the dominant enantiomer. When the plasma was replaced with buffer, the stereoselectivity in the RBC uptake of the enantiomers was abolished. This suggested that stereoselective protein binding may be responsible for this phenomenon. A direct measurement of the extent of binding of PPF enantiomers to rat and human plasma proteins further confirmed this. Moreover, the distribution of the enantiomers in RBCs was not affected by low temperatures or addition of ouabain, suggesting passive diffusion as the underlying mechanism. These results suggest that stereoselective red blood cell uptake may be responsible, at least in part, for the differences in the plasma pharmacokinetics of PPF enantiomers observed after the drug administration to humans and rats.
Stability of diltiazem in different biological fluids
Authors: McLean Angus M. , Cefali Eugenio A. , Roden Jennifer S. , Gonzalez Mario A. , Bialer Meir
Published: October 2006

The hydrolysis of diltiazem in biological fluids: whole blood, plasma, and gastric fluid was investigated under conditions considered close to the physiological situation. The most significant rate of hydrolytic degradation was found in whole blood (half‐life of 27h), followed by plasma (half‐life of 88h), while the least significant degradation rate was observed in gastric fluid (half‐life 153h). The kinetic profiles of diltiazem hydrolysis indicate that hydrolytic degradation in the biological fluids makes a minimal contribution to the clearance and disposition of the drug.
Kinetics of acetaminophen after single‐ and multiple‐dose oral administration as a gradient matrix system to healthy male subjects
Authors: Van Bomml Elvira M. G. , Raghoebar Maikel , Tukker Josef J.
Published: October 2006

The in vivo characteristics of two formulations of a recently developed controlled‐release system, the Gradient Matrix System (GMS‐1 and GMS‐2), with acetaminophen as a model drug compound have been determined in healthy volunteers both after separate single‐ and multiple‐dose administration. Values for the mean residence time (MRT) were increased from 5·2 h for an oral solution to 10·2 and 13·3 h for two GMS formulations after single dosing. Peak plasma concentrations were lower for the two GMS formulations after single dosing compared to the oral solution. The bioavailability, relative to the oral solution, was 91 per cent and 84 per cent for the two GMS formulations tested. After multiple dosing of one of the GMS formulations over 5 days, no change in AUC compared to the single dose AUC occurred. Steady state was reached within 2–3 days of twice daily dosing of the GMS formulation. The peak‐trough‐fluctuation (per cent PTF) was 44 per cent. No signs of dose dumping were observed in fasted subjects. A plateau‐like plasma drug concentration profile at steady state was maintained with the GMS formulation.
Comparative bioavailability of two flurbiprofen products: Stereospecific versus conventional approach
Authors: Jamali Fakhreddin , Collins David S. , Berry Brian W. , Molder Susan , Cheung Richard , McColl Kate , Cheung Helen
Published: October 2006

In this randomized, crossover study comparing the bioavailability of a film‐coated (Ansaid) with a sugar‐coated (Froben) 100 mg tablets of racemic flurbiprofen in 23 healthy young men, no significant differences were found for Cmax, tmax or AUC, using a nonstereoisomeric assay for flurbiprofen. Minor differences in the appearance of flurbiprofen in serum during the first 30‐min post‐dosing period were noted, with Ansaid appearing earlier than Froben. These differences likely reflect dissolution rate dissimilarity between the two products. Stereospecific determinations demonstrate a small (7·8 per cent) but significant difference in AUC of the active S‐configuration (Froben > Ansaid). No significant differences between Ansaid and Froben were found for tmax or Cmax for the S‐flurbiprofen. In bioequivalency studies of chiral drugs, stereospecific approaches provide a more accurate assessment of products.
Prednisone and prednisolone interconversion in the rabbit utilizing unbound concentrations
Authors: Hammarlund‐udenaes Margareta , Benet Leslie Z.
Published: October 2006

Prednisolone (POH) and prednisone (PO) were both administered via seven different intravenous infusions (three POH and four PO) in each of six rabbits to obtain steady state. Bolus doses of POH and PO were also administered to four of the rabbits. Plasma samples of POH and PO were analyzed by normal phase HPLC. Unbound concentrations of both compounds were estimated in each rabbit using equilibrium dialysis and computer fit of the nonlinear or linear binding. The unbound fraction of POH ranged between 3 and 15 per cent from tracer to total concentrations of 2000 μg−1. The unbound fraction of PO ranged between 23 and 34 per cent and appeared nonlinear for four of the rabbits. The mean apparent unbound clearances of POH ranged from 4·4 to 6·1 lh −1kg−1 and from 4·1 to 5·9 lh −1kg−1 for PO, and were dose‐independent for both compounds. The available fraction of POH from PO was 50 to 70 per cent and independent of dose. The available fraction of PO from POH averaged 44 per cent at the low infusion rate decreasing to 16 and 20 per cent at the medium and high infusion rates. Although saturability in the formation of PO from POH was noted, this nonlinear step is apparently not large enough to induce observable changes from linearity in the overall disposition of unbound POH.
Pharmacokinetics and bioavailability of papaverine HCl following intravenous, peroral, rectal, vaginal, topical and buccal administration in beagle dogs
Authors: Kraus Christian , Shaaya Ameera , Ulmer Joachim , Hutchings Dawn , Menon Anil , Sakr Adel , Ritschel Wolfgang A.
Published: October 2006

This in vivo study was designed to obtain bioavailability data and a definite pharmacokinetic profile of papaverine HCl in Beagle dogs following intravenous (IV), peroral (PO), rectal, vaginal, topical, and buccal administration of different papaverine HCl formulations. Blood samples were analyzed by high‐performance liquid chromatography. The pharmacokinetic parameters were determined using either a curve fitting program (RESID) or a compartment model independent program (AUC‐RPP). The plasma concentration‐time profiles show that papaverine HCl pharmacokinetics is best described by an open two‐compartment model. The absolute bioavailability of papaverine HCl was determined to be 57·2 per cent, 25·2 per cent, 53·2 per cent, 3·2 per cent and 7·5 per cent, respectively, following P.O., rectal, vaginal, topical and buccal administration.
Partially competitive inhibition of intestinal baclofen absorption by beta‐alanine, a nonessential dietary aminoacid
Authors: Polache A. , Plá‐delfina J. M. , Merino M.
Published: October 2006

In situ intestinal absorption of baclofen in the rat in the presence of beta‐alanine has been investigated. Through the perfusion of 0·50 mM baclofen solutions containing variable concentrations of the aminoacid (from 5 to 100 mM), a partially competitive inhibition of baclofen absorption was characterized: absorption rate pseudoconstants of the spasmolytic drug decrease as beta‐alanine concentration increases, until a limiting value is obtained (36·8 per cent of that found for baclofen alone). A computer method was developed in order to calculate parameters governing baclofen absorption in the presence of beta‐aminoacid, with the following results: Vm = 11·22 mM h−1; Km = 7·42 mM; Ki = 2·45 mM; α = 2·78; r = 0·998. Kinetic absorption parameters for betaalanine in the presence of 0·50 mM baclofen were also assessed: Vm = 49·88 mM h−1; Km = 12·16 mM; r = 0·998, which, as can be expected, do not significantly differ from those previously found in the absence of the spasmolytic. It is concluded that baclofen and beta‐alanine compete for the same intestinal carrier system, although the values of the interaction parameters, particularly Kt, can be more or less biased due to the limitations of the procedure and/or to the existence of some other carrier system for absorption. Possible practical implications of this phenomenon are briefly discussed.
A combined single and multiple dose pharmacokinetic study of oral isosorbide‐5‐mononitrate in healthy volunteers
Authors: Storm G. , Oosterhuis B. , Bron J. , Wittebrood A. J. , De Jong A. P. , Jonkman J. H. G.
Published: October 2006

Pharmacokinetics of 20 mg isosorbide‐5‐mononitrate (IS‐5‐MN) after single and multiple administration of two different tablet formulations were investigated in twelve healthy human subjects using an open, randomized, two‐way crossover experimental design. Pentacard® 20 mg tablets were compared with Ismo® 20 mg tablets.

After single‐dose administration, both preparations caused a rapid increase in IS‐5‐MN plasma levels with the peak plasma concentration occurring between 0·5 and 1·5 h. For both formulations, the mean plasma half‐life was found to be approximately 5 h after a single dose. In steady state during multiple dosing (t.i.d. at 8 h dosing intervals), a reduced elimination rate was observed. In line with this observation, the area under the plasma concentration‐time curve (AUC) for one 8 h dosing interval during multiple dosing was higher than the extrapolated AUC after a single dose. Based on statistical evaluation of the various relevant pharmacokinetic parameters calculated from the plasma concentrations occurring after single and multiple dosing, the tablet formulations are judged to be bioequivalent.
Use of a microbial model for the determination of drug effects on cell metabolism and energetics: Study of citrulline‐malate
Authors: Briand Joël , Blehaut Henri , Calvayrac Régis , Laval‐Martin Danielle
Published: October 2006

Euglena gracilis can be used as a microbial model to study the effect of drugs on lactate metabolism and gluconeogenetic synthesis. The cell growth and metabolism have been characterized in a 33 mM lactate medium, non‐supplemented or supplemented by dl‐malate or by l‐citrulline alone or by the compound formed by the stoichiometric combination of the two components: the citrulline‐malate (Stimol®). The malate of the complex accelerated the ammonium disappearance, while the citrulline facilitated the lactate consumption. A synergistic action of the complex, by comparison with the additive effects of the individual components, on most of the parameters studied was detected. A remarkable resistance to anoxia, and a quicker recovery under aeration of the cells supplemented with CM, were evident: after carbonation for 2 min the total nucleotides in the medium were increased by 44 per cent with an unchanged energy charge; and after a prolonged (20 min) anoxia followed by an aeration, the capacities of the cells to synthesize ATP in the presence of excesses of both ADP and phosphate were two‐fold higher in Stimol® treated cells than in control.