Abstract
Silkworm microorganism infection models are useful for screening novel therapeutically effective antimicrobial agents. In this study, we used silkworms to investigate the pharmacokinetics and metabolism of antimicrobial agents, in which cytochrome P450 plays a major role. The pharmacokinetic parameters of the antimicrobial agents were determined based on their concentrations in the hemolymph after administration. The parameters, such as half-lives and distribution volumes, in silkworm were consistent with those in mammalian models. In addition, antifungal agents with reduced therapeutic effectiveness due to high protein-binding capacities in mammalian serum exhibited similar features in silkworm hemolymph. Cytochrome P450 enzymes, which metabolize exogenous compounds in mammalian liver, were distributed mainly in the silkworm midgut. Most of the compounds metabolized by cytochrome P450 in humans are also metabolized in the silkworm midgut. These findings suggest that the pharmacokinetics of antimicrobial agents are fundamentally similar between silkworms and mammals, and that therapeutic effects in the silkworm infection model reflect the pharmacokinetics of the test samples.
Highlights
Continued development of novel antimicrobial agents is crucial toward combatting the spread of multi-drug resistant microorganisms, which has become a serious problem worldwide
The time-courses of the decrease in the concentrations of antibacterial agents such as chloramphenicol, tetracycline, vancomycin, and rifampicin, and antifungal agents such as micafungin and fluconazole, are biphasic as in mammals: alpha phase, when the compounds rapidly distribute into the organs, and beta phase, when the compounds are eliminated by metabolism and excretion (Fig. 1, raw data are provided in the supplementary Dateset)
We examined the pharmacokinetics of exogenous compounds in silkworm
Summary
Continued development of novel antimicrobial agents is crucial toward combatting the spread of multi-drug resistant microorganisms, which has become a serious problem worldwide. The half-maximal effective dose (ED50), i.e., the amount of the compound required to reduce survival of the microorganism by 50%, of clinically available antimicrobials is consistent between mammalian and silkworm models[2] Using this silkworm whole body assay system, we recently obtained the novel antibiotics lysocin E3 and ASP23974 by screening natural products, and a novel anti-methicillin resistant Staphylococcus aureus (MRSA) reagent, GPI0363, by screening a chemical library[5]. These compounds had therapeutic effects in a murine systemic infection model. Our results suggest that the therapeutic effectiveness of antimicrobials in the silkworm model reflect the pharmacokinetics of each compound, as in the case of mammalian models
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