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Biomedical subjects

F L Tse

Publications and source records attributed to F L Tse.

At least 55 records · Page 3Linked to original sources
PubMed1987

Pharmacokinetics of PN 200-110 (isradipine), a new calcium antagonist, after oral administration in man.

The pharmacokinetics of PN 200-110 (isradipine), a new calcium channel blocking agent, 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 5 mg every 8 h for 13 doses of [14C]PN 200-110. PN 200-110 was rapidly and almost completely (90-95%) absorbed from the gastrointestinal tract, although the estimated bioavailability was only 17% due to extensive first-pass metabolism. The pharmacokinetics of PN 200-110 appeared to be linear in the 5 to 20-mg dose range, as indicated by the dose-proportional blood levels of total radioactivity as well as the parent drug. Absorbed PN 200-110 was completely metabolized prior to excretion. The recovery of radioactivity after both the 5 and the 20-mg dose was virtually complete within the experimental period, with a renal:fecal excretion ratio of ca. 70:30. Repeated administration of [14C]PN 200-110 showed no change in pharmacokinetic characteristics. During the 5 mg thrice daily regimen, steady-state blood levels of parent drug were reached in 2 days while those of total radioactivity were reached in approximately 4 days. PN 200-110 and total radioactivity accumulated in blood by a factor of 2.1 and 3.4, respectively, indicating effective half-lives of 8.8 h and 16 h. The oral administration of [14C]PN 200-110 prescribed in the present study was safe and well tolerated.

Administration, Oral↗
PubMed1987

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.

Administration, Oral↗
PubMed1987

Disposition of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)- 1H-indole-3-methanol (59-801), a hypoglycaemic agent in rats, dogs and monkeys.

1. The disposition of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4 isoxazolyl)-1H-[3-14C]indole-3-methanol, an oral hypoglycaemic drug, has been studied in the rat, dog and monkey. 2. Oral doses of the drug were almost completely absorbed. The rate of absorption was rapid in the rat but less rapid in dog and monkey. Due to first-pass effect, the absolute bioavailability of the drug was incomplete and ranged from 60-75% in the monkey to 90% in the dog. 3. Intravenous as well as oral doses of the radiolabelled drug were rapidly and extensively distributed to body tissues. In rat, concentrations of radioactivity in all tissues except the brain exceeded, or were similar to, corresponding blood levels. Tissue and blood radioactivity levels were higher in female than in male rats, and increased disproportionately with increasing dose. 4. The drug was partially metabolized before excretion, the extent of metabolism ranging from ca. 50% in the rat to 90% in the monkey. Although only a limited number of animals were used, metabolism appeared to be saturable within the dose range studied in dog and monkey but not in rat. The half-life of unchanged drug was dose-independent in the rat (1.4 h), but tended to increase with increasing dose in the dog (4.1-7.2 h) and monkey (2.1-4.5 h). 5. In all three species, the administered radioactivity was recovered predominantly in urine, although biliary excretion also played an important role in drug elimination. Recovery of dose was essentially complete within 1-2 days.

Animals↗
PubMed1987

Pharmacokinetics and metabolism of alpha-[(dimethylamino)methyl]-2- (3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3-methanol, a hypoglycemic agent, in man.

1. The pharmacokinetics and metabolism of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl) -1H-[3-14C]indole-3-methanol, a new hypoglycemic agent, have been studied in 15 healthy male volunteers who received an oral dose of 50 or 200 mg. 2. The drug was rapidly and almost completely absorbed intact from the gastrointestinal tract. 3. Compared with the 50 mg dose, the 200 mg dose yielded less than proportionally higher blood concentrations of radioactivity and unchanged drug. This phenomenon has been observed previously in the rat and was probably due to an increase in drug distribution volume with increasing dose, since the metabolism and excretion patterns of the drug appeared to be dose-independent. 4. The drug was partially metabolized prior to excretion. Approximately 40% of the dose was recovered intact, almost exclusively in urine. The major metabolic pathway of the drug was by conjugation with glucuronic acid, while oxidation of the indole ring gave rise to a relatively minor metabolite. 5. The recovery of administered radioactivity was virtually complete within the experimental period, with a renal:faecal excretion ratio of ca 80:20. The elimination half-life of unchanged drug was 25-30 h while that of total radioactivity was 33-35 h.

Adolescent↗
PubMed1986

Effect of butalbital and phenobarbital pretreatment on antipyrine clearance in the rat.

The disposition kinetics of antipyrine after a single i.v. dose (75 mg/kg) of [14C]antipyrine were examined in control rats and in rats pretreated with butalbital and phenobarbital. Blood antipyrine data indicated that daily administration of phenobarbital (50 mg/kg) for 14 days resulted in significantly more rapid elimination of antipyrine than that observed after equal doses of butalbital, which was in turn significantly faster than the control values. Results of additional antipyrine tests after phenobarbital pretreatment for 2 and 5 days showed considerable enzyme induction after only 2 days of exposure to phenobarbital; the mean antipyrine clearance after the 2-day pretreatment was not significantly different from those after the 5- and 14-day pretreatments. The data suggested that the maximum increase in antipyrine clearance, ca. 190% of the control value, was achieved after approximately 5 daily doses of phenobarbital and maintained until the end of the 14-day pretreatment period. The subsequent decline in the induced enzyme activity, assessed by the antipyrine clearance values on days 1, 3, 6, and 9 post-phenobarbital treatment, appeared to be mono-exponential with a half-time of 3.8 days. Thus, the enzyme activity would return to baseline at ca. 15 days after the last dose of phenobarbital. In these studies, consistent increases in liver weight with increasing antipyrine clearance were observed, while no apparent relationship between antipyrine distribution volume and barbiturate pretreatment was found.

Animals↗
PubMed1985

Pharmacokinetics of dihydroergotamine following subcutaneous administration in humans.

The pharmacokinetics of dihydroergotamine was studied following a 1.5-mg subcutaneous dose of the mesylate salt in six healthy volunteers. Plasma and urine dihydroergotamine, determined using a specific radioimmunoassay, were simultaneously fitted to equations consistent with a two-compartment open model. The drug was rapidly absorbed from the injection site; peak plasma concentrations of 3-8 ng/ml were observed within 15-45 min of dosing. Half-lives for the rapid and slow phases of decline in plasma dihydroergotamine were 0.95 and 7.26 h, respectively. The overall volume of distribution was 14.6 l/kg. The plasma clearance and renal clearance values were 1814 and 91 ml/min, respectively, indicating that 5% of the dose was excreted unchanged in the urine. Comparison of the results of the present study to published data confirmed that dihydroergotamine is eliminated from the body predominantly by metabolism.

Adult↗
PubMed1984

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.

Adult↗
PubMed1984

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.

Animals↗
PubMed1984

Factors contributing to variability in drug pharmacokinetics. I. Absorption.

Apart from the physical and chemical properties of a drug, and also the dosage form in which it is presented, many other factors may affect the absorption of orally administered compounds and give rise to variable systemic availability. Three such factors, gastrointestinal (GI) disease, drug-drug interactions, and drug-food interactions are considered here. Although information regarding these factors, particularly GI disease, is scarce and sometimes conflicting, it is clear that they may give rise to variable drug absorption. The wide spectrum of effects on different drugs precludes the application of general rules and guidelines in drug therapy in most cases. Drugs, dosage forms, and various interactions should be considered individually. Also the types of interactions described in this review must be combined with other factors to be discussed later in this series when considering the influence of variable absorption, distribution, metabolism, and excretion on drug pharmacokinetics and clinical efficacy.

Bacterial Infections↗
PubMed1984

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.

Absorption↗
PubMed1984

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.

Animals↗
PubMed1983

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.

Animals↗
PubMed1983

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.

Administration, Oral↗
PubMed1983

Food interactions affecting the absorption of analgesic and anti-inflammatory agents.

Food interactions affect the absorption of most analgesic and anti-inflammatory agents. Of the 18 compounds that have been examined, only prednisone and phenazone were unaffected by food. The absorption of indomethacin and phenacetin was decreased, while the absorption of diftalone and proquazone was increased. The remaining drug entities exhibited delayed absorption. The major factor influencing delayed or reduced absorption appears to be delayed stomach-emptying in the presence of food. However, delayed stomach-emptying may also promote absorption of diftalone and proquazone by permitting greater dissolution of these drugs before they pass into the small intestine. Reduced local gastrointestinal irritation of nonsteroidal anti-inflammatory agents in the presence of food, together with reduced fluctuation in circulating drug levels, probably outweighs any disadvantage of impaired absorption.

Analgesics↗
PubMed1982

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.

Administration, Oral↗
PubMed1982

Estimating the fraction reabsorbed in drugs undergoing enterohepatic circulation.

A simple method of estimating the extent of biliary recycling using blood level and cumulative biliary excretion data from control and bile duct-cannulated animals is described. The method was tested in rats following an intravenous dose of [14C] temazepam. It was shown that 62% of the drug excreted in the bile of control rats was reabsorbed during each enterohepatic cycle, contributing to the secondary peak blood concentrations and a prolonged elimination half-life.

Absorption↗
PubMed1982

A practical method for monitoring drug excretion and enterohepatic circulation in the rat.

An improved experimental design for studying the enterohepatic circulation of drugs in a pair of bile duct-duodenum cannula-linked rats is described. By housing the rats in individual metabolism cages and using a peristaltic pump to immediately deliver bile secreted by the donor directly into the duodenum of the recipient, the method permits a realistic approximation of biliary excretion and reabsorption in intact animals for periods up to 96 hours.

Animals↗