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Disposition of moxalactam and N-methyltetrazolethiol in rats and monkeys
Abstract:
The disposition of moxalactam (MOX) and N-methyltetrazolethiol (NMTT) in rats and monkeys after intravenous injection was investigated, focusing on the in vivo liberation of NMTT, by using [NMTT-14C]MOX and [14C]NMTT. After [NMTT-14C]MOX injection, MOX levels in plasma quickly became high in both rats and monkeys and then declined, with half-lives at the beta phase of 18.8 and 67.1 min, respectively. The levels of NMTT liberated from MOX were much lower than those of MOX, but the apparent elimination was significantly slow. The levels of MOX and NMTT in rat liver were almost comparable but lower than those in plasma. With [14C]NMTT administration, the level of NMTT in plasma declined, with half-lives at the beta phase of 21.5 min in rats and 54.0 min in monkeys. After [NMTT-14C]MOX injection, most of the radioactivity was excreted in urine as MOX, with 11% of the dose in rats and 8% of the dose in monkeys eliminated as NMTT until 24 h. Total biliary excretion was 26% of the injected radioactivity in rats, and most of it was due to MOX. In one monkey, the total biliary excretion was only 0.2% of the injected radioactivity. With [14C]NMTT administration, most radioactivity was excreted in the urine as unchanged NMTT in both animals. Oral administration in rats showed that part of the biliary-excreted MOX was degraded to NMTT in the intestine and then absorbed. Repeated administration of [NMTT-14C]MOX to rats did not change the levels of MOX and NMTT in plasma or liver nor did it change the excretion profiles. Thus, accumulation of MOX and NMTT did not occur.
Insights
Moxalactam (MOX) is eliminated quickly in rats and monkeys, but the liberated N-methyltetrazolethiol (NMTT) clears slowly. Neither MOX nor NMTT accumulated with repeated dosing, indicating low toxicity risk.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Toxicology
Background:
- Moxalactam (MOX) is a beta-lactam antibiotic.
- N-methyltetrazolethiol (NMTT) is a side chain of MOX with known toxic potential.
- Understanding the disposition of MOX and NMTT is crucial for assessing MOX safety.
Purpose of the Study:
- To investigate the in vivo disposition and liberation of NMTT from MOX in rats and monkeys.
- To determine the pharmacokinetic profiles of MOX and NMTT.
- To assess the potential for accumulation of MOX and NMTT.
Main Methods:
- Intravenous and oral administration of radiolabeled MOX ([NMTT-14C]MOX) and NMTT ([14C]NMTT) in rats and monkeys.
- Plasma and tissue level measurements using radioactivity.
- Urinary and biliary excretion analysis.
- Repeated dose administration studies.
Main Results:
- MOX exhibited rapid plasma clearance with short half-lives in both species.
- Liberated NMTT levels were lower than MOX but showed significantly slower elimination.
- Urinary excretion was the primary route for MOX and NMTT elimination.
- Oral administration showed intestinal degradation of MOX to NMTT.
- No accumulation of MOX or NMTT was observed after repeated dosing.
Conclusions:
- MOX is rapidly eliminated, but NMTT liberation and slow clearance warrant attention.
- The pharmacokinetic profile suggests a low risk of MOX and NMTT accumulation.
- Further studies may be needed to fully elucidate NMTT's long-term effects.