Propoxyphene and norpropoxyphene: influence of diet and fluid on plasma levels.

The influence of various test meals and ingested fluid volumes on the bioavailability and pharmacokinetics of propoxyphene and its major metabolite norporpoxyphene has been studied in healthy human subjects. The absorption of drug was delayed by all test meals, but the overall efficiency of absorption was either not affected or was slightly increased. Increased fluid volume intake decreased propoxyphene bioavailability. Plasma levels of metabolite correlated well with levels of unchanged drug, particularly in the first 2 hr after dosing, but were not markedly influenced by treatments.

Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers.

The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [3H] fluvastatin in three different studies: a single-dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple-dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (greater than 90%) absorbed from the gastrointestinal tract, although the estimated bioavailability from the 2- and 10-mg doses was only 19 to 29% because of extensive first-pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2- to 10-mg dose range, as indicated by dose-proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half-lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40-mg doses of [3H]fluvastatin resulted in no time-related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first-pass effect on fluvastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of compound 58-112, a potential skeletal muscle relaxant, in man.

The pharmacokinetics of 4-[(3-methoxyphenyl)methyl] -2,2,6,6-tetramethyl-1-oxa-4-aza-2,6-disilacyclohexane (Sandoz compound 58-112), a new chemical entity with a unique myotonolytic effect, was studied in 12 healthy male volunteers who received an oral dose of 50 or 100 mg of the 14C-labeled drug. Serial blood and breath samples and complete urine and feces were collected for 120 hours after dosing. All samples were analyzed for total radioactivity while the blood and urine were also assayed for unchanged compound 58-112. Measurable blood radioactivity levels were observed at 0.5 hour, and peak concentrations were attained at 1 to 2 hours after dosing. The absorption of the radioactive doses was complete and appeared linear in the 50-100 mg range, as indicated by blood 14C levels that were proportional to the dose. The 50- and 100-mg doses also resulted in virtually identical excretion patterns, with 95 per cent of the administered radioactivity recovered within 9 hours, almost exclusively in the urine. However, the disproportionately higher blood concentrations of unchanged compound 58-112 after the 100-mg dose could suggest saturable presystemic metabolism in the liver. Simultaneous fitting of all data in the 100-mg dose study to a pharmacokinetic model showed that unchanged compound 58-112 was distributed into a central and a peripheral compartment and was eliminated entirely by metabolism, the distribution and elimination half-lives being 0.5 and 3.9 hours, respectively. The metabolite(s) was distributed into one homogeneous space, and its elimination half-life was 0.1 hour, with a renal:fecal clearance ratio of approximately 96:4.

Pharmacokinetics of orally administered tizanidine in healthy volunteers.

The pharmacokinetics of tizanidine, a new centrally acting muscle relaxant, have been studied in 18 normal male volunteers who received orally a single 5 mg dose, a single 20 mg dose, or repeated administration of 4 mg every 8 hr for 13 doses of [14C]tizanidine. Serial blood and breath samples and complete urine and feces were collected and analyzed for total radioactivity as well as intact tizanidine. Tizanidine was rapidly and almost completely absorbed from the gastrointestinal tract, although the estimated bioavailability was only 21% due to extensive first-pass metabolism. The pharmacokinetics of tizanidine appeared to be linear in the 0-20 mg dose range, as indicated by the dose-proportional blood levels of total radioactivity as well as of parent drug. Absorbed tizanidine was almost completely metabolized before excretion, the major excretory route being via the kidneys. The terminal half-lives of tizanidine and radioactivity were ca 3 hr and 61 hr, respectively, and 76%-77% of the administered radioactivity was recovered within 120 hr. Repeated administration of [14C]tizanidine resulted in no apparent change in pharmacokinetic characteristics. During the 4 mg q 8 hr regimen, blood levels of tizanidine reached steady state after only 2 or 3 doses, whereas those of total radioactivity approached steady state after approximately 4 days. The degree of accumulation of radioactivity, unlike that of parent drug, was inconsistent with the terminal half-life, but instead implied a shorter effective half-life of ca. 16 hr. It appears that the terminal phase of the blood radioactivity profile represents a metabolite that is reversibly bound to and slowly released from a specific tissue depot, and that this binding involves a finite amount of drug regardless of the dose. The oral administration of [14C]tizanidine prescribed in the present study was safe and well tolerated.

Theophylline bioavailability in the dog.

The bioavailability of theophylline following single oral doses of a theophylline capsule, a theophylline tablet, and an aminophylline tablet in beagle dogs was compared against an intravenous standard. Plasma theophylline levels after oral and intravenous drug administration were described by the one-compartment open model. The onset of theophylline absorption from the oral products was rapid. While the theophylline tablet showed a slower absorption rate than the capsule or the aminophylline tablet, all three products appeared to be completely bioavailable.

Prednisolone bioavailability in the dog.

With a fasted dog as an animal model, the bioavailability and pharmacokinetics of prednisolone were studied following rapid intravenous injection and oral dosing of a prednisolone sodium phosphate solution and also following oral doses of prednisolone as tablets and a slurry. Hydrolysis of the phosphate ester to prednisolone in the body is extremely rapid and complete, thus permitting accurate calculation of the distribution volume of prednisolone. Enteral absorption of prednisolone from a slurry is superior to that from prednisolone tablets and from a prednisolone sodium phosphate solution. Reduced absorption from tablets, compared to the slurry, is probably due to tablet disintegration characteristics; reduced absorption from the solution is probably due to poor membrane permeability of the ionized drug. Information obtained from a single animal may indicate the need for expanded studies in humans.

Biliary excretion of [14C]temazepam and its metabolites in the rat.

The excretion of temazepam and its N-desmethyl metabolite, oxazepam, and their respective O-conjugates was examined following a single intravenous dose of [14C]temazepam to two groups of bile fistula rats, with and without bile replenishment to the animals via duodenal cannulae. During an 8-hr collection period, the two groups produced virtually identical bile volumes, and there were no significant differences between them in the amount of total radioactivity, free temazepam, or the identified metabolites in the bile, as determined by TLC and liquid scintillation counting. Elimination of the radioactive dose was rapid during 0-8 hr, with a half-life of approximately 1 hr. Approximately 85-90% of the administered radioactivity was recovered in the bile: less than 1% as free temazepam, 3% as oxazepam, and approximately 10% as their O-conjugates.

Binding of fluvastatin to blood cells and plasma proteins.

The binding of fluvastatin, an inhibitor of hydroxymethylglutaryl coenzyme A reductase, to plasma proteins and red blood cells of rat, dog, and human in vitro was determined by ultrafiltration. Additionally, the stereospecificity of fluvastatin binding to proteins and the potential interaction between fluvastatin and the highly protein bound drugs warfarin, salicylic acid, and glyburide were investigated. Only a small fraction of fluvastatin in blood was taken up by the blood cells, amounting to 19-33% in the rat and < or = 15% in dog and humans. The plasma:blood fluvastatin ratio in these species at 37 degrees C was > or = 1.4. In human blood, this ratio was temperature independent. In the plasma concentration range 25-50,000 ng/mL, fluvastatin was > or = 98% bound to proteins. The binding was concentration dependent in the rat, but not in the dog and human. Both enantiomers of fluvastatin were > 99% bound in normal human plasma, the binding of each being unaffected by the presence of the other. A major fluvastatin-binding protein in human plasma was albumin, whereas binding to alpha 1-acid glycoprotein was relatively weak and concentration dependent. At therapeutic concentrations in normal human plasma, the protein binding of fluvastatin (0.1 microgram/mL) was unaffected by warfarin (1-10 micrograms/mL), salicylic acid (50-150 micrograms/mL), and glyburide (0.1-1 micrograms/mL). Similarly, fluvastatin had no influence on the binding of these compounds. In diluted human albumin solution (29 microM), bound fluvastatin was displaced by all three co-solutes tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of mode of intravenous administration and blood sample collection on rat pharmacokinetic data.

The influence of the mode of intravenous dosing and blood sample collection on the pharmacokinetics of 4-[(3-methoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2, 6-disilacyclohexane hydrochloride (I) was studied in the rat. Blood samples obtained from the tail and by exsanguination following injection of the 14C-labeled drug into the caudal vein, the jugular vein, and the heart were analyzed for total radioactivity, and the concentration profiles from the different treatments were compared. Dosing and sampling from the tail vein resulted in significantly different blood levels (and related pharmacokinetic parameters) when compared to other methods, probably attributable to a local depot effect. Intracardiac administration tended to cause higher drug levels in the heart than intravenous doses, although no significant differences were found between the respective blood concentrations. The results showed that caudal vein injection is a simple and adequate method of intravenous administration in rats designated for exsanguinated blood and tissue collection. For serial blood sampling in individual animals, the dose may be given via the jugular vein and the blood collected from the cut tail. These methods require little or no surgical preparations and are particularly suitable for prolonged sampling in studies where a relatively large number of animals are involved.

Effect of caffeine on circulating theophylline levels in beagle dogs.

The pharmacokinetic interactions of caffeine with theophylline were examined in two beagle dogs by administering 100 mg of aminophylline intravenously, 3 weeks before and immediately after repeated oral doses of caffeine. Serial plasma samples were analyzed for caffeine and theophylline simultaneously by high-performance liquid chromatography. Upon multiple oral dosing, 100 mg every 12 hr for 7 days, the caffeine half-life increased slightly in one dog but decreased in the other. As predicted from single-dose data, caffeine accumulation in plasma after repeated doses was slight, while plasma levels of the N-demethylated metabolite, theophylline, rose to about three times the initial values. After rapid intravenous doses of aminophylline, the theophylline half-life was 5-7 hr, which decreased slightly when the drug was administered concomitantly with caffeine during steady state of caffeine. The theophylline volume of distribution (0.75 liter/kg) was unaffected by caffeine. On the other hand, an acute aminophylline injection prolonged the elimination half-life and increased the apparent volume of distribution of caffeine, causing little overall change in its plasma clearance. The results suggested that interactions between theophylline and caffeine may be attributed to changes in drug distribution and drug elimination characteristics.

Determination of the chiral isomers of CGS 26214, a synthetic thyromimetic agent, in human plasma using microbore chiral chromatography-tandem mass spectrometry.

CGS 26214 is a racemic compound having cholesterol-lowering activity in rats, dogs, and monkeys. This compound has two equipotent chiral components CGS 28934(-) and CGS 28935(+). An analytical challenge was to develop a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the analysis of the chiral components in human plasma following clinical doses of 1 mg or less. Several issues had to be addressed in order to devise a LC/MS/MS assay for the above compounds. First, the compounds were esters and susceptible to hydrolysis under experimental conditions. Second, a lower limit of quantitation (LLOQ) of 0.4 ng/ml was needed. Third, positive electrospray ionization of CGS 26214 did not yield sufficient sensitivity needed for the studies in humans. Consequently, LC/MS/MS conditions were optimized for negative ion mode of detection. Fourth, sample preparation steps proved to be critical in order to reduce the possibility of microbore chiral-HPLC column (100 x 1.0 mm i.d.) obstruction, chromatographic deterioration, and matrix mediated electrospray ion suppression. Although the present method addressed the above challenges, its major drawback was limited sample throughput capability. Nonetheless, the method was successfully applied to generate plasma concentration-time profiles for human subjects after oral doses (0.9 mg) of the racemate as well as the optically pure isomers.

Enterohepatic circulation of radioactivity following an oral dose of [14C]temazepam in the rat.

The enterohepatic circulation of radioactive material after administering [14C]temazepam was evaluated in three sets of male Wistar strain rats connected in pairs by bile duct-duodenum cannulae. After a single oral dose (10 mg kg-1) to the donor rat, the excretion of radioactivity in the urine and faeces of both rats and in the bile of the recipient rat was determined. Mean total recovery of the administered radioactivity was 92.2%. Based on the amount remaining in the donor rat (gastrointestinal tract and faeces), 81.7% of the dose was absorbed by the donor. The total amount recovered from the recipient, 69.4% of original dose (85.1% of donor's absorbed dose), represented the amount excreted in the donor's bile. Similarly, 54.1% of the original dose (77.9% of the transferred biliary excretion from donor) was reabsorbed by the recipient, and the biliary excretion from this animal (45.9% original dose) accounted for 86.% of the amount reabsorbed.

Relative absorption of tryptophan ethyl ester amide derivatives with various fatty acid chains in the dog.

Sandoz compound 57-118 is a mixture of tryptophan ethyl ester amide derivatives (analogues I-V) possessing one of five fatty acid chains which differ in chain length, configuration, or the degree of unsaturation. The relative absorption of each of the five analogues was investigated in the dog following single oral doses of the homologous mixture containing one 14C labelled analogue. It was shown that the extent of absorption of analogue I and its trans-isomer, II, both with a mono-unsaturated fatty acid chain, were similar. An additional double bond in the fatty acid moiety (analogue III) facilitated gastrointestinal absorption. On the other hand, saturated fatty acid chains appeared to render the molecule less efficiently absorbed; the extent of absorption being dependent on the chain length. Thus, analogue V with 16 carbon atoms on the fatty acid chain was better absorbed than IV with 18.

Bioavailability of isradipine in young and old rats: effect of mode of administration.

The bioavailability of isradipine has been examined in 7- and 52-week-old rats after oral (12.5 mg kg-1) or intravenous (2.5 mg kg-1) doses as a solution and administration of various doses (1.8-85.5 mg kg-1) in the diet. Serial plasma samples were obtained from each rat and the drug concentration was determined by radioimmunoassay. Absorption from the dose given by gavage was rapid but when administered in a drug diet mixture, isradipine appeared in the plasma slowly and in a manner reflecting the feeding pattern. Its absolute bioavailability from the drug-diet mixture averaged 3% over the dose range tested. By gavage its bioavailability was enhanced to 5% of dose with peak plasma values approximately 7 times higher than from a comparable dose in the diet. The low oral bioavailability of isradipine in the rat was most likely due to extensive first-pass metabolism. The decline in plasma concentrations was biexponential, with a mean terminal half-life of 3.6-3.7 h after oral or intravenous dosing. The pharmacokinetic characteristics of isradipine examined were independent of the age of the rat, except that its volume of distribution decreased with age. The older rats also showed a greater inter-animal variability in isradipine bioavailability from the drug-diet mixture.

Effect of food, fluid and dosage form on the absorption of 52-522, a potential antianxiety agent, in the dog.

The absorption of 52-522 in the dog was studied by measuring blood concentrations of radioactivity after single oral doses of [14C] 52-522 in a capsule with and without water, also as a food-drug mixture, and a solution in polyethylene glycol 400. Absorption was rapid, and its rate moderate with no significant differences in peak times among treatments. The extent of absorption was lowest after the capsulated [14C] 52-522. The solution dose gave elevated blood concentrations, that were statistically significantly different when compared with the capsules. Hence, it appears that the absorption of [14C] 52-522 is governed by the degree of dispersion of drug in the dosage form.

Interspecies similarities in the disposition of 3H-dihydroergotamine following subcutaneous administration in man and rabbits.

The disposition of dihydroergotamine methanesulfonate following single subcutaneous doses was studied in man and the rabbit using radiotracer techniques. 3H-Dihydroergotamine was almost immediately and completely absorbed from the injection site; peak blood radioactivity levels were attained within 1 h of drug administration in both species. The disappearance of radioactivity from blood was biphasic, with t 1/2,alpha and t 1/2,beta values of 2.9 and 16.9 h, respectively, in man and 2.9 and 14.7 h, respectively, in the rabbit. Apparent volumes of distribution were 18.9 Liter/kg in man and 30.4 Liter/kg in the rabbit. The excretion pattern of dihydroergotamine and its metabolites was also similar for the two species, with biliary elimination being the predominant route. At 4-5 days postdosing, 80-85% of the administered radioactivity was recovered in the feces and urine. The rabbit appears to be an adequate animal model for the study of dihydroergotamine pharmacokinetics in man.