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J F Thiercelin

Publications and source records attributed to J F Thiercelin.

32 records · Page 2Linked to original sources
PubMed1982

A method for estimating within-individual variability in clearance and in volume of distribution from standard bioavailability studies.

Bioavailability studies are commonly undertaken, and most, because they involve subjects taking repeated doses of a drug, contain information on intraindividual variability in pharmacokinetics. However, because in such studies bioavailability itself is unknown, it is difficult to resolve which pharmacokinetic parameters vary within individuals. A mathematical model is presented which permits estimation of variability in clearance and in volume of distribution. When applied to pooled data arising from five theophylline bioavailability studies, this model has given statistical evidence that clearance of theophylline is inherently more variable within individuals (coefficient of variation, 13%) than volume of distribution (8%). As a result, use of the measurement AUC-beta rather than AUC as a more precise index of bioavailability is justified in studies where beta is measured with reasonable precision. The model could be applied to estimation of within-batch within-person variability in bioavailability.

Biological Availability↗
PubMed1980

Evaluation of the absorption from 15 commercial theophylline products indicating deficiencies in currently applied bioavailability criteria.

The bioavailability of theophylline from alcoholic and aqueous oral solutions was compared to that from an intravenous dose in 12 normal adults. The alcoholic elixir surprisingly gave rise to a significantly greater (114 +/- 14%, mean +/- SD) amount absorbed than did the intravenous dose. The aqueous solution (99 +/- 8%) and intravenous dose were statisticlly indistinguishable in this respect, and, furthermore, the extent of absorption from a 300-mg dose of the aqueous solution was 99 +/- 10% of that from a 500-mg dose, and not statistically different. The aqueous solution was thus employed in three subsequent studies as a standard with which to compare 13 different types of theophylline tablets, all marketed in the United States. Of the 13 tablets, eight showed bioavailability statistically distinguishable from that of the standard. Nevertheless, for only two tablets could it be claimed with 95% confidence level that the bioavailability was less than 95%. For none can it be stated at this confidence level that the bioavailability is less than 90%. Bioavailability studies should include criteria of clinical significance in addition to criteria of statistical significance. Contrary to the usual rationale behind choice of a bioavailability standard, nine of the 12 uncoated tablets appeared to allow more rapid absorption of theophylline than did the standard oral solution, an aqueous syrup. Increasing the dose of syrup decreased the rate of theophylline absorption. Orally administered drug solutions may have properties more absorption rate limiting than the disintegration of many brands of tablet.

Absorption↗
PubMed1980

Evaluation of the absorption from some commercial sustained-release theophylline products.

Absorption of theophylline from three commerical products labeled as sustained release was compared to the absorption from a standard uncoated tablet (Searle 200-mg aminophylline tablet) in a single-dose study. Aminodur tablets (Cooper) and Slophyllin Gyrocap capsules (Dooner) had bioavailability (100.2% +/- 19.8% and 98.5% +/- 13.8%) statistically indistinguishable from that of the standard but showed significantly slower absorption (peak times of 10.4 +/- 2.8 and 4.36 +/- 1.35 hr) and lower peak plasma concentrations (13.9 +/- 4.5 and 22.6 +/- 3.5 micrograms/ml/g dose) than the standard (tpeak, 1.52 +/- 0.45 hr; Cpeak, 28.1 +/- 6.2 micrograms/ml/g dose). The time of the plasma concentration peak (2.47 +/- 1.38 hr) after a dose of Tedral S.A. (Warner/Chilcott) was not statistically different from that after the standard, but both the peak concentration (16.0 +/- 3.9 micrograms/ml/g dose) and availability (76.0 +/- 18.4%) were. Multiple-dose projections from single-dose data indicate that of the three test products only Aminodur maintains reasonably constant interdose plasma levels during 12 hoursly dosing. With an 8 hourly dosing schedule Gyrocaps also might be satisfactory. Reasonable predictions of the plasma concentrations arising from Aminodur doses have been made using a single-compartment body model and assuming input from an outer followed by an inner layer of the tablet.

Biological Availability↗
PubMed1980

Evaluation of the absorption from some commercial enteric-release theophylline products.

In a single-dose bioavailability study, Wales, Robinson, Columbia, and Choledyl (Warner/Chilcott) enteric-coated tablets all allowed a bioavailability of theophylline (99% +/- 25%, 102% +/- 23%, 103% +/- 18%, and 98% +/- 15%; mean +/- SD, n = 12) statistically indistinguishable from that of the standard uncoated tablet (Searle 200 mg aminophylline). Only the Wales and Choledyl tablets (7.6, 4.2 hr) could be shown (p < 0.5) to generate a peak plasma theophylline concentration later than the standard (1.4 hr). All tablet brands demonstrated a significant lag time before appearance of theophylline in the plasma, and both Wales and Choledyl tablets also had a (tpeak-tlag) statistically different from that of the standard. Despite misleading indications from the mean plasma profile (plasma concentrations at each sampling time averaged over all subjects), plasma data from the individual participants and in vitro dissolution data show that, while release of theophylline from the Wales tablet might be inordinately slow, this is not a sustained-release preparation. Of the enteric-coated tablets only the Columbia product allowed significant levels in the first sample after dosage. Five of the 18 Columbia doses gave rise to 40-99% of the peak concentration in the 1-hr sample. In vitro, it takes 39 +/- 14 min for 40% of the theophylline content of Columbia tablets to dissolve in simulated intestinal fluid. Suprisingly rapid delivery of an enteric-coated tablet to the duodenum would appear to be required to allow a significant percentage of theophylline to be dissolved and absorbed before 1 hr. None of 12 Columbia tablets tested in vitro, however, allowed dissolution of more than 1.2% of their theophylline content during 1 hr immersion in simulated gastric fluid. Since once in intestinal fluid Columbia tablets appear to dissolve more rapidly than the other enteric products, it is not clear whether the five Columbia tablets in question had imperfections or wheter, in fact, this tablet brand more closely than the others represents the ideal of immediate release once in the duodenum. Plasma samples should be taken as early as 15 min after dosage when evaluating the bioavailability of enteric release products.

Adult↗
PubMed1977

The influence of cigarette smoking and sex on theophylline disposition.

The effects of cigarette smoking and sex on theophylline clearance, elimination rate constant, and apparent volume of distribution were examined in 28 healthy, young adults given single oral doses of theophylline or aminophylline. Two-way analysis of variance showed no sex effect but a significant effect of smoking habit on theophylline clearance and elimination rate constant. Neither sex nor smoking had an effect on the apparent volume of distribution. The respective mean clearance, elimination rate constant, and volume of distribution were, in nonsmokers, 0.040 +/- 0.008 (SD) liter per hour per kg, 0.084 +/- 0.015 hr-1, 0.47 +/- 0.08 liter per kg; heavy smokers, 0.063 +/- 0.019 liter per hour per kg, 0.129 +/- 0.045 hr-1, 0.50 +/- 0.06 liter per kg; and ex-smokers, 0.051 +/- 0.10 liter per hour per kg, 0.108 +/- 0.025 hr-1, 0.49 +/- 0.08 liter per kg. Cigarette smoking appeared to induce theophylline metabolism as reflected by the mean theophylline half-life in smokers (5.4 hours) versus nonsmokers (8.3 hours). The effect of cigarette smoking on theophylline clearance may be an important consideration in the clinical use of the drug.

Adult↗
PubMed1976

[Pharmacokinetics of DL-norephedrine 14C in the rat].

After i.v. administration of DL-norephedrine 14C to the rat (535 mug/kg), approximately 75% of the radioactivity was eliminated during the first 18 hr in the urine. Beside the unchanged drug (71.5% of the total urinary radioactivity), the main metabolite was alpha-methyloctopamine (18%), a parahydroxylated derivative of which 68% were excreted as glucuronide conjugates. Kinetic studies of DL-norephedrine in different organs showed that the affinity of tissues for the amine did not change with time. Captation was important and rapid in lungs, adrenals, spleen and heart. The brain was marked by a slow increase of drug level during the first 2 hr. However, the terminal semi-exponential kinetic slopes of DL-norephedrine concentration showed that the elimination processes of the drug were the same in each tissue. The affinity of tissues for alpha-methyloctopamine was shown to be much more specific; its uptake was higher in organs which are rich in adrenergic nerve endings (heart, adrenals and spleen). These results confirm the role of this hydroxylated amine as a false neurotransmitter. A whole body autoradiography in the mouse showed an important uptake of DL-norephedrine 14C in salivary glands and periocular structures.

Animals↗
PubMedDate not supplied

Pharmacokinetic interactions of progabide with other antiepileptic drugs.

The influence of progabide, a new antiepileptic drug, on the pharmacokinetic profiles of phenobarbital, phenytoin, carbamazepine, and valproic acid was evaluated in four separate studies, each including six young healthy volunteers. The pharmacokinetic parameters of the associated antiepileptic drugs were measured before and after repeated administration of progabide (600 mg t.i.d.) for 15 days. A significant reduction of the total body clearance of both phenytoin and phenobarbital and a higher Cmax value of carbamazepine epoxide and phenobarbital were observed. No modifications were noticed for the kinetic profiles of carbamazepine and valproic acid. These modifications may be of clinical relevance and suggest that, as a general rule, when progabide is added to an established treatment with phenobarbital or phenytoin or carbamazepine, an adjustment of previous posology may be necessary.

Adult↗