VOL.30 S-1 CHEMOTHERAPY Table 1 Dose of CTT and subjects i. v.: Intravenous bolus injection d. i. v.: Intravenous drip infusion i. m.: Intramuscular injection Fig. 1 Schedule for examination of CTT, 1.0g ~5 i. v. Only GOT, GPT, Al- P and blood glucose were examined
Table 2 Test item Fig. 2 Chemical structure of CTT and its tautomer (1) Clinical symptoms. Subjective, Objective, Allergy, Others (2) Blood pressure (3) Electrocardiogram (4) Body temperature (5) Hematology : WBC, RBC, Hb, Ht, Platelet, WBC differential count (6) Blood chemistry : Total protein, A/G ratio, GOT, GPT, Al-P, LAP, ƒá-gtp, LDH, Total cholesterol, Blood sugar, BUN, Creatinine, Na, K (7) COOMBS' test : Direct, Indirect (8) Urinalysis : Sugar, Acetone, Protein, (9) Plasma level of CTT (10) Urinary level of CTT Bilirubin, Occult blood, Urobilinogen, Sediments Table 3 Measurement by high performance liquid chromatography (HPLC) HPLC conditions Column : Nucleosil Cl 8(5ƒÊm), Column temp. 150mm ~4mm i. d. Mobile phase : 8% Acetonitrile- 92% 0.1 M Sodium dihydrogen phosphate (ph 3.0) Pressure : 2,000 psi Flow : 1.2ml/ min Detector : UV (280nm) Chart speed : 5mm/ min
VOL.30 S-1 CHEMOTHERAPY Fig. 3 Plasma level of CTT Fig. 4 Plasma level of CTT Table 4-1 Plasma level of CTT, A single dose, i. v. (Group 1, 3) Mean }S. E. Đg/ml Table 4-2 Plasma level of CTT, Multidose, i. v. (Group 2, 4) Mean }S. E. Đg/ml
Table 4-3 Plasma level of CTT, Multidose, iv. (Group 7, 8) (1) Group 7: 1.0g ~5 i. v.(n= 3) Mean }S. E.ƒÊg/ ml, n. d.: Not detectable (2) Group 8: 1.0g ~11 i. v.(n= 4) Mean }S. E.ƒÊg/ ml Table 4-4 Plasma level of CTT, A single dose, d. i. v.(group 5, 6) Mean }S.E.ƒÊg/ ml, n. d.: Not detectable Table 4-5 Plasma level of MT, A single dose, i. m.(group 9) Mean }S. E.ƒÊg/ ml
VOL.30 S-1 CHEMOTHERAPY Table 5 Pharmacokinetic parameters of CTT
Fig. 5 Plasma level of CTT, Multidose, 1.0g ~5 i. v. Fig. 6 Plasma level of CII, Multidose, 1.0g ~11 i. v.
VOL.30 S-1 CHEMOTHERAPY Fig. 7 Urinary excretion of CTT Table 6-1 Urinary excretion of CU, A single dose, i. v.(group 1, 3) Mean }S. E.
Table 6-2 Urinary excretion of CTT, Multidose, i. v.(group 2, 4) Mean }S. E. Table 6-3 Urinary excretion of CTT, Multidose, i. v.(group 7, 8) (1) Group 7: 1.0g ~5 i. v.(n= 3) Mean }S. E. a) Rec. : Recovery (%) Cum. rec. : Cumulative recovery (%) b) Concn.(ƒÊg/ml) : Concentration (ƒêg/ml)
VOL.30 S-1 CHEMOTHERAPY (2) Group 8: 1.0g ~11 i. v.(n= 4) Mean }S. E. a) Rec. : Recovery (%) Cum. rec. : Cumulative recovery (%) b) Concn. (Đg/ml) : Concentration (Đg/ml) Table 6-4 Urinary excretion of CTT, A single dose, d. i. v.(group 5, 6) Mean }S. E. Table 6-5 Urinary excretion of CTT, A single dose, i. m.(group 9) Mean }S. E.
Table 7 Urinary recovery of CTT and its tautomer
VOL.30 S-1 1) TACHIBANA, A.; M. KOMIYA, Y. KIKUCHI, K. YANO& K. MASHIMO Pharmacological studies on YM09330, a new parenteral cephamycin derivative. 19th Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstr. No. 563, 1979 2) YANO, K.; K. SUZAKI, M. SAITO, M. TODA, T. SAITO& S. MITSUHASHI: In vitro and in vivo antibacterial activities of YM09330, a new cephamycin derivative. ibid. Abstr. No. 564, 1979
PHASE- I CLINICAL STUDY ON CEFOTETAN (YM09330) MASARU KOYAMA and KEIICHI NAKAGAWA Department of Internal Medicine, Tokyo Kyosai Hospital MASAYUKI KOMIYA, YASUHIRO KIKUCHI, AKIO TACHIBANA and KUNIICHIRO YANO Central Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd. Cefotetan (CTT, YM09330), a new parenteral cephamycin antibiotic, was administered to 28 healthy male volunteers to study its safety and pharmacokinetics. Doses of cefotetan were I) single intravenous bolus injection (i. v.), of 0.5 g II) 0.5 g i.v. twice a day for one day III) single 1.0 g i. v. IV) 1.0 g i. v. twice a day for one day V) single intravenous drip infusion (d. i. v.) of 2.0 g VI) single 3.0 g d. i. v. VII) VIII) 1.0 g i.v. twice a day for 2.5 days 1.0 g i.v. twice a day for 5.5 days IX) single intramuscular injection (i. m.) of 0.5 g Results were as follows; 1) No abnormalities attributable to cefotetan were noted in any examined items such as symptoms, blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, COOMBS' test and urinalysis. 2) The mean plasma levels of cefotetan 15 min after dosing were 85.2 and 171 /2g/ml for 0.5 g i. v. and 1.0 g i. v. respectively. And they were slowly declined to 7.6 and 17.4 Đg/ml at 8 h after dosing. The average were calculated to be 3.11 h and 3.40 h for 0.5 g i.v. and1.0 g i. v. respectively by the two compartment open model. Plasma levels of cefotetan were not accumulated even when cefotetan was intravenously administered with 11 consecutive doses of I g at intervals of 12 h. 3) Seventy- five `eighty-five% of cefotetan were excreted in 24 h urine after dosing, and approximately 5% of cefotetan were found in the form of the tautomer. No metabolites of cefotetan were detected in urine.