Drugs 49 (Suppl. 2): 341-343, 1995 0012-6667/95/0002-0341 /SO 1.50/0

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Gallbladder Tissue Concentrations, Biliary Excretion and Pharmacokinetics of OPC-17116 Hiroshi Tanimura, Kazuhisa Uchiyama and Hideo Kashiwagi Department of Gastroenterological Surgery, Wakayama Medical College, Wakayama, Japan

OPC-17116 is a new oral carboxylic acid quinolone antibacterial agent synthesised by Otsuka Pharmaceutical Co., Ltd. Antibacterial as­sessment has shown that OPC-17116 possesses a broad spectrum of in vitro activity against Gram­positive and Gram-negative bacteria, including an­aerobes, with particularly potent activity against aerobic Gram-positive bacteria and anaerobes.[l]

Preliminary pharmacokinetic assessments in healthy adult volunteers have shown that plasma OPC-17116 concentrations increase dose depend­ently after oral administration at doses of 100 to 400mgP]Its elimination half-life (10 to 12 hours) is longer than that of most quinolones, thus indicat­ing the possibility of once-daily administrationP] No drug accumulation was noted after repeated administration. [2]

A high rate of tissue distribution has been observed after oral administration in animal studiesJ3] In human studies, the compound was excreted pri­marily via the bile; urinary excretion of unchanged compound was 10 to 12% of the administered dose during the period 0 to 72 hours after oral administration.

Since OPC-17116 possesses a broad spectrum of antibacterial activity, it may be clinically useful in the treatment of biliary tract infections. This study was conducted to determine the pharmacoki­netics of OPC-17116, and particularly its concen­trations in bile and gallbladder tissue, and the ex­tent of its biliary excretion.

1. Methods

OPC-17116 Concentrations in Gallbladder Tissue and Bile: OPC-17116 was administered orally at a dosage of 300mg once daily, starting 3 days before surgery, to 6 patients who were to un­dergo cholecystectomy. During the laparotomy, samples of blood, gallbladder tissue, and gall­bladder bile were collected to assess OPC-17116 concentrations.

OPC-17116 Pharmacokinetics in Bile: In 1 patient with an indwelling percutaneous trans­hepatic cholangio-drainage (PTCD) tube, single oral doses of OPC-17116 150 and 300mg were administered 24 hours apart. Bile concentrations of unchanged drug and metabolites were de­termined during the periods from 0 to 2 hours, 2 to 4 hours, 4 to 8 hours and 8 to 12 hours after oral administration.

Pharmacokinetics of OPC-17116 Metabolites in Serum and Bile: A single oral dose of OPC-17116 300mg was administered to 2 patients under­going PTCD treatment for bile duct cancer.

All drug concentrations were determined by high performance liquid chromatography.

Recovery Rates of OPC-17116 in Urine and Bile: A single oral dose of OPC-17116 300mg was administered to 2 patients undergoing PTCD treat­ment for obstructive jaundice due to gastric and colonic cancers. Bile and urinary concentrations of unchanged drug and metabolites were determined.

342

2. Results

OPC-17116 Gallbladder Tissue and Bile Con­centrations: The results are shown in figure 1. OPC-17116 concentrations of 1.8 mg/L (mean 0.9 mg/L), 9.6 mg/kg (mean 5.6 mg/kg), and 189 mg/L (mean 50.8 mg/L) were attained in the serum, gall­bladder tissue, and bile, respectively, at 2 to 5 hours. The common bile duct bile concentration, determined in 1 patient, was 6.7 mg/L. Drug con­centrations in gallbladder tissue' and bile were higher than those in blood and generally exceeded minimum inhibitory concentrations (MICs) against most relevant pathogens.[l]

OPC-17116 Pharmacokinetics in Bile: During the period from 0 to 12 hours, the concentrations of unchanged OPC-17116 and its main metabolite (4'-sulfate) reached a maximum of 2.93 and 5.19 mg/L, respectively, both during the period from 4 to 8 hours for the single 150mg dose, and 7.93 mg/L during the period from 2 to 4 hours and 17.21 mg/L during the period from 4 to 8 hours, respec­tively, for the single 300mg dose. The values for area

Tanimura et al.

under the curve (AUC) at 12 hours forOPC-17116 and its 4'-sulfate metabolite were 20.7 and 72.1 mg-hlL, respectively, for the 150mg dose, and 47.7 and 199.1 mg-h/L, respectively, for the 300mg dose. These results suggest that OPC-17116 dis­plays dose-proportional pharmacokinetics in bile over an oral dose range of 150 to 300mg.

Pharmacokinetics of OPC-17116 Metabolites in Serum and Bile: In the first patient, the concen­trations of unchanged OPC-17116 were 0.79 mg/L in serum at 4 hours and 13.8 mg/L in bile during the period of 2 to 4 hours. The total concentration of all metabolites in bile was 6.8 mg/L during the period of 4 to 8 hours. In the second patient, the concentrations of unchanged drug in serum at 4 hours and in bile at 4 to 8 hours were 0.58 mg/L and 2.85 mg/L, respectively, Only the glucuronic acid conjugate was found in the bile in this patient; no other metabolites were detected. Additionally, concentrations of unchanged compound in plasma and bile were higher than those of metabolites at all measurement times.

Serum Gallbladder t issue Gallbladder bile and common bile duct bile

189 200 0 Serum • 100 0 Gallbladder tissue

• Gallbladder bile

• Common bile duct bile . -50.8

• Mean • c; • ~ • 0 9.6

6.7 • -' 10 0

0, --00-5.6 • .s 0 c

.Q 0 0

"§ 0 1: 0

Q) 0 <..>

~-o-O.9 c a U

0 0

0.1 0 2 4 6 0 2 4 6 0 2 4 6

Time (hours)

Fig. 1. Gallbladder tissue, bile, and serum concentrations of OPC-17116 after oral administration of 300mg for 3 days.

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Extended Abstract

OPC-17116 Urinary and Biliary Excretion Rates: The concentration of unchanged OPC-17116 in bile collected during the period from 0 to 24 hours was 2.85 mg/L in 1 patient. Recovery rates for OPC-17U6 and its metabolites in urine were 11.3 and 12.1 % (total 23.4%), respectively.

In the other patient, the concentration of unchanged OPC-17116 in bile collected during the period from 0 to 24 hours was 3.13 mg/L. Re­covery rates for OPC-17116 and its metabolites in urine were 17.6 and 8.4% (total 26.0%), respectively.

3. Conclusion

OPC-17116 demonstrated a high rate of pene­tration into the gallbladder tissue and bile. Concen­trations of unchanged drug exceeded MICs for the main causative pathogens in biliary tract infec­tions. These results suggest that OPC-I7116 may be effective for the treatment of biliary tract infections.

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References 1. Ohguro K, Ohnishi H, Kubo N, et al. OPC-17116, a novel

broad-spectrum 5-methyl quinolone derivative: antibacterial activity in vitro [abstract no. 1461]. Program and Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 1991: 342

2. Uematsu T, Nagashima S, Takiguchi Y, et al. OPC-17116, a new quinolone: phase I Study [abstract no. 1481]. Program and Abstracts of the 31st Interscience Conference on Anti­microbial Agents and Chemotherapy, Chicago, IL, 1991: 346

3. Akiyama H, Koike M, Nii S, et al. OPC-17116, an excellently tissue-penetrative new quinolone: pharmacokinetic profiles in animals and antibacterial activities of metabolites [abstract no. 1477]. Program and Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago,IL,1991:345

Correspondence and reprints: Prof. Hiroshi Tanimura, De­partment of Gastroenterological Surgery, Wakayama Med­ical College, 27-Schichibancho, Wakayama City 640, Japan.

Drugs 49 (Suppl. 2) 1995