[Pharmacokinetics of tebipenem pivoxil, a novel oral carbapenem antibiotic, in experimental animals].
Pharmacokinetics of tebipenem pivoxil (TBPM-PI), a novel oral carbapenem antibiotic, were known in various laboratory animal. (1) In mouse, rat, dog and monkey, TBPM-PI were absorbed quickly, and the bioavailability was (71.4, 59.1, 34.8 and 44.9%, respectively. (2) TBPM-PI was quickly converted to tebipenem (TBPM), an active form of TBPM-PI. Through blood circulation, TBPM was distributed into the kidney at a high concentration and eliminated quickly. There was no other tissue than the kidney, in which TBPM was highly distributed and remained for a long time. In addition, low penetration to the central nervous system was confirmed. The penetration ratio of TBPM to ELF, that is the ratio of ELF concentration to plasma concentration of TBPM, was 21.8 +/- 14.7%. (3) Serum protein bindings of TBPM in the range of 0.1-100 microg/ml were 90.4-98.3% for mouse, 78.5-90.0% for rat, 15.7-18.7% for dog, 35.3-39.3% for monkey and 59.7-73.9% for human. (4) In vitro metabolism was investigated in plasma, liver S9 fractions and small intestinal S9 fractions derived from infant and adult animals. TBPM-PI was transformed into TBPM quickly in any matrices. It was confirmed that absorbed TBPM-PI was quickly transformed into TBPM or LJC 11,562 (opened ring TBPM) in the plasma after oral administration of 14C-TBPM-PI to infant or adult rat and monkey. TBPM-PI and opened ring TBPM-PI was not detected in plasma and urine samples. In rat and monkey, the oral absorption, distribution, metabolite and excretion of TBPM-PI were not so much different between infant and adult animals. (5) Liver metabolic enzyme system was little affected by 7-days repeated administration of 1-100 mg/kg TBPM-PI. IC50 values of TBPM-PI and TBPM for human CYP isoforms were estimated to be 100 microg/ml or higher. (6) After single oral administration of 10 mg/kg 14C-TBPM-PI to rat, 36.9-42.7% and 58.3-62.2% of radioactivity was excreted to urine and feces, respectively, by 120 hours after administration. The majority of dosage was excreted out of body by 48 hours after administration. After single intravenous administration of 10 mg/kg 14C-TBPM, 87.4% and 11.4% of radioactivity was excreted in urine and bile, respectively, by 24 hours after administration. The majority of dosage was excreted out of body by 4 hours after administration.
Kijima
Koji
K
Pharmacokinetic Labs., Applied Pharmacology Research Labs., Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd.
Morita
Jun
J
Suzuki
Katsuyoshi
K
Aoki
Makoto
M
Kato
Kazuhiko
K
Hayashi
Hiroyuki
H
Shibasaki
Shigeki
S
Kurosawa
Tohru
T
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D005260:Female; D006801:Humans; D007223:Infant; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D055815:Young Adult
D001798:Blood Proteins; D015780:Carbapenems; D065607:Cytochrome P-450 Enzyme Inhibitors; C500135:tebipenem