Pharmacokinetics of anti-infectious reagents in silkworms

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.

A novel silkworm infection model with fluorescence imaging using transgenic Trichosporon asahii expressing eGFP

“…Optimizing the experimental condition to enable more reproducible measurement of LD 50 values is a future subject. Silkworms are useful for evaluating the pharmacokinetics and toxicity of compounds [31][32][33][34][35] . In mammalian animals, organs such as the intestinal tract, liver, and kidney govern the pharmacokinetics of drugs.…”

“…In mammalian animals, organs such as the intestinal tract, liver, and kidney govern the pharmacokinetics of drugs. Recent studies revealed that silkworms have functionally similar organs that affect drug pharmacokinetics and toxicity [32][33][34][35] . Many in vitro and in vivo analyses revealed that the absorption of compounds from the silkworm intestinal tract is similar to that in mammals 26,27,31,43 .…”

“…The ED 50 values of antibiotics in silkworms are similar to those in mice 26 . The difference in the total clearance, volume of distribution, and half-life values of anti-microbial agents such as chloramphenicol, tetracycline, vancomycin, rifampicin, micafungin, and fluconazole is less than 10-fold between silkworms and mammals 35 . The LD 50 values for compounds are also similar between silkworms and mammals 28,32 .…”

“…Avirulent mutants that exhibit lower pathogenicity against silkworms also exhibit lower pathogenicity in infection experiments in mice. Many studies using antimicrobial drugs, toxic compounds, and natural products demonstrate that the therapeutic effects, pharmacokinetic parameters, and toxicity are similar between silkworms and mammals [31][32][33][34][35] . Moreover, lysocin E 36 , nosokomycin 37 , ASP2397 38 , and GPI0363 34 were identified by exploratory research using a silkworm infection model from microbial culture broths and chemical libraries as novel antimicrobial compounds that show therapeutic effects in mouse infection experiments.…”

Facilitating Drug Discovery in Human Disease Models Using Insects

“…18,19) Many in vitro and in vivo analyses revealed that the absorption of compounds from the intestinal tract of silkworms is similar to that of mammals. [15][16][17]20) The total clearance, volume of distribution, and half-life values of antimicrobial agents such as chloramphenicol, tetracycline, vancomycin, rifampicin, micafungin, and fluconazole differ by less than 10-fold between silkworms and mammals. 21) Toxicity to animals is quantitatively indicated by the LD 50 value, the dose of a compound required to kill half of an experimental group.…”