Biomedical subjects

T Yashiki

Publications and source records attributed to T Yashiki.

At least 55 records · Page 3Linked to original sources

PubMed1986

Estimation of drug absorption rates using a deconvolution method with nonequal sampling times.

A method affording direct estimation of the drug absorption rate from blood level data using arbitrary time intervals has been derived based on the staircase input principle. In the derivation, the drug was assumed to follow linear kinetics where the plasma concentration of the drug after an impulse input is expressed by a multiexponential function. Drug absorption was assumed to occur at a constant rate during each subsequent sampling interval. The absorption rate profiles obtained by the method using several numerical examples were expressed as a set of rectangular pulses. Divergence in the profiles reflected blood sampling measurement errors rather than errors due to the deconvolution. Smoothing of the rate profiles by calculating the mean of the absorption rates between adjacent time intervals gave realistic results. Absorption rate profiles for theophylline obtained by the method using published data gave information on the initiation and termination of the absorption as well as the extent of absorption from the dosage form.

Humans↗

PubMed1986

Preparation of 1-acyloxyethyl esters of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoe thy l)-1H-tetrazol-5-yl]thio]-methyl]ceph-3-em-4-carboxylic acid (cefotiam) and their oral absorption in mice.

In a separate study on the orally active acyloxymethyl esters (1) of 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl) - 1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid (cefotiam, CTM), we have shown, by quantitative structure-oral bioavailability (BA) relation analysis, that the R2 group in the acyl group R2CO must have both an adequate lipophilicity (Hansch's lipophilic parameter, pi) and steric hindrance (Taft's Es value). However, to satisfy these requirements, a complex alkyl group R2 must be employed, the ester of which is difficult to synthesize and has unique metabolic fate. In this study, we selected and prepared the 1-acyloxyethyl esters (2) of CTM instead of 1 to avoid R2 groups that are too complicated. We found that the esters (2) gave improved oral BAs over 1: the 1-(3-methyl-valeryloxy)ethyl ester (2h) showed the highest peak plasma CTM level (Cmax) comparable to that obtained after subcutaneous injection of CTM. The 1-(cyclohexylacetoxy)ethyl ester (2t), the 1-(2-ethylbutyryloxy)ethyl ester (2j), and 2h showed BAs near 100%. For these esters (2), good correlations were also observed among the pi, the Es values of R2, and the log Cmax and log BA in the analysis of the quantitative structure-oral bioavailability relation: an ester having an alkyl group as R2 with a pi value of 3.07 or 3.08 and a Es value of -1.04 or -1.29 gave the highest Cmax or BA, respectively. As expected, the optimal pi values are almost the same as those obtained with 1 but the optimal Es values are larger (Es = -2.07). Thus, it has been confirmed by preparing 1-acyloxyethyl esters (2) of CTM that the oral bioavailability of CTM can further be improved without preparing acyloxymethyl esters (1) with a complicated acyl group.

Administration, Oral↗

PubMed1984

Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (leuprolide) in rats. IV: Evaluation of the vaginal absorption and gonadotropin responses by radioimmunoassay.

The vaginal absorption of leuprolide (a potent luteinizing hormone-releasing hormone analogue), which has the potential for producing regression of hormone-dependent tumors as well as high gonadotropin-releasing and ovulation-inducing activities, was evaluated in rats by radioimmunoassay. Gonadotropin (luteinizing hormone and follicle-stimulating hormone) release was concomitantly determined. Although leuprolide disappeared rapidly from the serum after intravenous administration (the biological half-lives were 8.4 min in the alpha-phase and 33.2 min in the beta-phase), long-lasting serum levels were observed when the analogue was administered vaginally. The vaginal absorption was enhanced by adding citric acid to the test solution. The absolute bioavailability, estimated by the AUC of serum leuprolide levels, was 25.8% over 6 h and 38.0% over 12 h in the 5% citric acid solution (pH 3.5). The sustained release of gonadotropin was also obtained after vaginal administration of the analogue. A linear dose absorption correlation of leuprolide was obtained in the range of 10-1000 micrograms/kg in an aqueous solution or methylcellulose jelly. The release of gonadotropin showed a plateau level at greater than 10 micrograms/kg, which corresponds to an effective dose for antitumor activity. The vaginal absorption of leuprolide varied with the estrous cycle, but this effect was eliminated by prior subcutaneous pretreatment with the analogue.

Absorption↗

PubMed1983

Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (leuprolide) in rats II: mechanism of absorption enhancement with organic acids.

Organic acids such as citric acid enhance the vaginal absorption of luteinizing hormone-releasing hormone, the potent analogue (leuprolide), and insulin. The mechanism of this absorption enhancement was investigated with leuprolide and hydrophilic markers such as phenol red and Evan's blue. The absorption of the analogue was increased by lowering the pH of the solution and increased more by adding citric, succinic, tartaric, and malonic acids. The absolute bioavailability after vaginal administration of the 5% citric acid solution was 16.7% at pH 3.5 and 38.4% at pH 1.8. The enhancing potency of the absorption correlated well with the chelating ability of the organic acids. The vaginal absorption of phenol red was also enhanced with citric acid and edetic acid, but the enhancing effect of edetic acid was eliminated by adding equimolar calcium ion. These results suggest that the acidifying and chelating abilities of the acids may result in a potent enhancement of the vaginal absorption of leuprolide. A leakage experiment using Evan's blue on the vaginal membrane indicated that the blood-vaginal epithelium barrier was loosened with the administration of citric acid; this change was overcome rapidly.

Absorption↗

PubMed1983

Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (leuprolide) in rats III: Effect of estrous cycle on vaginal absorption of hydrophilic model compounds.

The effect of estrous cycle stages on vaginal absorption was determined by the use of insulin, phenolsulfonphthalein, and salicylic acid as hydrophilic model compounds. Absorption of these compounds was markedly affected by the stage, possibly due to the change of transport rate through the pore-like pathways. The absorption of phenolsulfonphthalein during proestrus and estrus is roughly one-tenth of that during metestrus and diestrus. An increase of the nonionized form of salicylic acid, produced by a lowered pH, resulted in an enhancement of absorption during proestrus and diestrus; higher contribution of the transport through the cell membrane possibly reduced an effect of the estrous cycle. However, consecutive daily administration of leuprolide halted the cycle at diestrus and reduced the cycle effect on the vaginal absorption of phenolsulfonphthalein; when the treatment was started at any of the four stages of the cycle, vaginal absorption was enhanced approximately 20%, with less variance than that observed in normal diestrous rats.

Animals↗

PubMed1983

Desensitization of gonadotropin-releasing response following vaginal consecutive administration of leuprolide in rats.

The vaginal absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide), and the gonadotropins (luteinizing hormone and follicule-stimulating hormone)-releasing response after continuous vaginal and subcutaneous administration of the analog to rats were determined by the radioimmunoassay. A marked suppressive effect on the gonadotropin-releasing response along with long-lasting serum levels of leuprolide were paradoxically observed after consecutive 3-d vaginal administration of the analog at doses of 1 microgram/kg or greater. Pituitary function recovered progressively with cessation of the treatment but was not complete 4 d after cessation. Continuous vaginal and subcutaneous infusion resulted in an almost complete inhibition of both gonadotropins response. It is suggested that effective desensitization of the pituitary gonadotropin response is elicited by continuous administration of leuprolide and, therefore, the vaginal administration resulting in prolonged serum levels of the analog could be preferable as a self-administration method for medical treatments such as anti-tumor therapy and birth control.

Absorption↗

PubMed1983

Regression of rat mammary tumors by a potent luteinizing hormone-releasing hormone analogue (leuprolide) administered vaginally.

Potent luteinizing hormone-releasing hormone analogues are known to cause regression of hormone-dependent mammary tumors. We have observed that high and long-lasting serum levels of a potent luteinizing hormone-releasing hormone analogue [desglycyl10-(D-leucyl6) luteinizing hormone-releasing hormone ethylamide, leuprolide] resulted from vaginal administration which effectively caused down regulation in the pituitary by chronic treatment. Regression of 7,12-dimethylbenz(a)-anthracene-induced mammary tumors in Sprague-Dawley rats by consecutive daily vaginal administration of leuprolide was investigated. In untreated rats, 71% of tumors were growing at 8 weeks, whereas after i.p. injection of leuprolide (500 micrograms/kg) all tumors were regressing 2 weeks after commencement of treatment and 86.7% of tumors disappeared by 8 weeks. Vaginal administration of 100 micrograms/kg for 8 weeks produced regression in 80% of tumors and disappearance in 35%. The vaginal administration of a higher dose (500 to 5000 micrograms/kg) produced highly significant antitumor effects [regression in 82.2 +/- 4.0% (S.E.) and disappearance in 52.9 +/- 2.1%]. These results are consistent with the effects produced by ovariectomy. Whereas 13 and 7 new tumors appeared in untreated rats and those treated vaginally with leuprolide (100 micrograms/kg), respectively, only one or two tumors appeared in i.p. and vaginally (above 500 micrograms/kg) treated rats during treatment. Histological classification of the mammary tumors after treatment indicated therapeutic effects similar to those shown by tumor size determination. Thus, it was concluded that vaginal application of leuprolide at doses above 500 micrograms/kg might be a potentially useful method for antitumor therapy.

Animals↗

PubMed1982

Vaginal absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide) in rats I: absorption by various routes and absorption enhancement.

The absorption of a potent luteinizing hormone-releasing hormone analog (leuprolide) through different routes was evaluated by determining the ovulation-inducing activity in diestrous rats. Vaginal administration showed the greatest potency among nonparenteral routes and was followed successively by rectal, nasal, and oral administration. Mixed micellar solution with monoolein-bile acids improved the intestinal absorption of leuprolide, and nasal absorption was enhanced by adding sodium glycocholate, surfactin, or polyoxyethylene 9 lauryl ether, but these bioavailabilities were still insufficient. The vaginal absorption was enhanced by organic acids: citric, succinic, tartaric, and glycocholic; the absolute bioavailability increased to approximately 20%. The vaginal absorption from jellies, as practical dosage forms, yielded sufficient activity of leuprolide, but absorption was slightly reduced with highly polar polymers or with higher concentrations of polymers. It was concluded that vaginal administration of leuprolide can be a rational dosage method for a long-term antitumor therapy.

Absorption↗

PubMed1982

Correlation of the bioavailability of diazepam from uncoated tablets in beagle dogs with its dissolution rate and bioavailability in humans.

The bioavailability of diazepam (I) in uncoated tablets in beagles was tested using tablets tested previously in humans. The correlations of the dissolution rates and bioavailabilities of these tablets in humans and beagles were examined. The plasma level of N-desmethyldiazepam (II), the main metabolite of I, was used as an index of bioavailability after p.o. administration of uncoated tablets of I, because I is rapidly metabolized. Thus the plasma level of I is very low, and AUCs (areas under plasma level-time curves) calculated from plasma levels of II were related to the dose of I (2-10 mg). With different tablets, the rates and extents of bioavailability of I differed significantly in beagles, but only the rate of bioavailability showed significant differences in humans. The rank orders of tablets, based on the blood levels of II soon after p.o. administration of the tablets were the same, but other parameters of bioavailability of I in the tablets were quite different in beagles and humans. Consequently, there was no significant correlation between the bioavailabilities of I in beagles and humans. The gastric fluid of beagles is almost neutral, and the bioavailabilities of the tablets in beagles correlated well with the dissolution rates of I determined at pH 4.6, but not at pH 1.2. The differences in the bioavailabilities of I in humans and beagles were attributed to differences in transit time in the gastrointestinal tract and/or in the volume of the gastrointestinal fluid.

Animals↗

PubMed1980