[Studies on the metabolic fate of isepamicin sulfate (HAPA-B). II. Accumulation of HAPA-B after multiple administration in rats].

The accumulation of isepamicin sulfate (HAPA-B) in tissues and plasma was studied upon multiple intramuscular and intravenous administrations of 25 mg/kg of HAPA-B daily for 8 or 15 days to male rats. Shapes of plasma concentration curves in multiple intramuscular and intravenous administrations were very similar to that in a single administration. Drug concentrations in kidney at 24 hours after 8- and 15-multiple administrations through both routes were 3 to 4 and 4 to 5 times as high as that after a single administration. The concentration in kidney increased by multiple administrations for 8 days, but did not increase so highly there after till the 15-multiple administrations. On the other hand, the elimination of HAPA-B from kidney after multiple administrations was similar to that after a single administration. The accumulation of HAPA-B upon multiple administration was also observed in lung, heart, spleen and liver, but peak concentrations of the drug in these tissues were lower than that in kidney.

[Studies on the metabolic fate of isepamicin sulfate (HAPA-B). I. Absorption, distribution, metabolism and excretion in rats].

Absorption, distribution, metabolism and excretion of isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, after a single administration were studied in rats. After intramuscular administration of HAPA-B at a dose level between 6.25 and 100 mg/kg, the drug was rapidly absorbed to reach the peak in 0.10 to 0.21 hour (Tmax). The maximum drug concentration in the plasma (Cmax) and the size of the area under the plasma concentration-time curve (AUC) depended on dose levels. The HAPA-B disappeared rapidly from the plasma after intramuscular and intravenous administrations with biological half-lives (T1/2) from 0.41 to 0.47 hour with intramuscular administration and from 0.23 to 0.35 hour with intravenous administration. Peak time after intramuscular, intraperitoneal and subcutaneous administration of HAPA-B at a dose of 25 mg/kg were 0.18, 0.24 and 0.37 hour, respectively. Maximum drug concentrations in plasma were 64.15, 53.71 and 40.39 micrograms/ml and biological half-lives of the drug were 0.47, 0.73 and 0.87 hour, respectively. The HAPA-B was distributed rapidly into tissues, especially at a high level into kidney after intramuscular or intravenous administration of 25 mg/kg. Concentrations in lung and heart were next to that in kidney, but were not higher than plasma concentrations. The drug was excreted mainly into the urine after intramuscular and intravenous administration within 24 hours and approximately 79 to 90% of the administered amount was excreted. Meanwhile, the excretion of HAPA-B into the bile was 0.1% or less during the first 24 hours after intramuscular and intravenous administration. Bioautograms of thin layer chromatographs of 0 approximately 6 hours urine samples after intramuscular administration showed single bands with the identical Rf value to the standard HAPA-B. No difference between male and female was observed in the fate of the administered HAPA-B through intramuscularly. The shape of the plasma concentration curve and the urinary excretion after intramuscular administration of HAPA-B at the dose of 25 mg/kg was similar to those of amikacin (AMK) and gentamicin. Tissue concentrations after intramuscular and intravenous administration of HAPA-B were also similar to AMK.

[Studies on the metabolic fate of isepamicin sulfate (HAPA-B). III. Intramuscular, intravenous and drip intravenous administration of HAPA-B in rabbits].

Absorption, distribution, metabolism and excretion of isepamicin sulfate (HAPA-B) were studied following intramuscular, intravenous and drip intravenous administration at doses of 6.25, 25 and 100 mg/kg to rabbits. Plasma concentrations of HAPA-B following intramuscular, intravenous and drip intravenous administration depended on dose levels. Biological half-lives (T1/2), body clearance (Clt) and areas under plasma concentration-time curves (AUC) for different routes of administration were similar in all 3 routes. A theoretical curve for drug concentrations vs. time was obtained using pharmacokinetic parameters calculated from drug concentrations in plasma following a 45-minute drip intravenous administration. From the curve, it was estimated that 60 to 90 minutes would be required to achieve a similar maximum drug concentration in plasma by drip intravenous administration to that obtained by intramuscular administration. Thus, drug concentration patterns obtained following intramuscular administration could be duplicated in drip intravenous administration by regulating the length of time for infusion. The concentration of HAPA-B in tissues obtained following a 15-minute drip intravenous administration reached maximum after 15 minutes at a level higher than that achieved by intramuscular administration, but an hour later, concentrations in tissues including the kidney decreased to similar levels obtained following intramuscular administration and patterns of concentration decrease for drip intravenous administration and intramuscular administration were quite similar to each other thereafter. The drug was rapidly excreted into the urine following any of the 3 routes, and urinary recoveries in 24 hours were 75 approximately 92% of dose amounts for all dose levels tested. Bioautograms on thin-layer chromatographs of 0 approximately 6 hours urine samples obtained following an intramuscular administration of the drug showed a single biologically active bands with similar Rf values to HAPA-B itself. No active metabolite of the drug was detected in the urine.

[Studies on the metabolic fate of isepamicin sulfate (HAPA-B). V. Plasma concentrations of HAPA-B in dogs after multiple administrations].

Plasma concentrations after a single or multiple intramuscular administrations of isepamicin sulfate (HAPA-B) at dose levels of 6.25, 25 and 100 mg/kg to male and female dogs were measured by microbiological assay, and were also compared with those of amikacin at dose levels of 25 and 100 mg/kg. Shapes of plasma concentration curves after multiple administrations of HAPA-B were very similar to those after single administrations at all dosage levels tested. On the other hand, the shape of plasma concentration curve after multiple administration of amikacin at 100 mg/kg was markedly different from that after a single administration.