Pharmacokinetics of Azalomycin F, a Natural Macrolide Produced by Streptomycete Strains, in Rats.

Su He,Duoduo Zhang,Wenjia Zhao,Wenqing Tu,Ganjun Yuan,Kui Hong,Tongke Zhang,Peibo Li

doi:10.3390/molecules26216464

Abstract

As antimicrobial resistance has been increasing, new antimicrobial agents are desperately needed. Azalomycin F, a natural polyhydroxy macrolide, presents remarkable antimicrobial activities. To investigate its pharmacokinetic characteristics in rats, the concentrations of azalomycin F contained in biological samples, in vitro, were determined using a validated high-performance liquid chromatography–ultraviolet (HPLC-UV) method, and, in vivo, samples were assayed by an ultra-high performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) method. Based on these methods, the pharmacokinetics of azalomycin F were first investigated. Its plasma concentration-time courses and pharmacokinetic parameters in rats were obtained by a non-compartment model for oral (26.4 mg/kg) and intravenous (2.2 mg/kg) administrations. The results indicate that the oral absolute bioavailability of azalomycin F is very low (2.39 ± 1.28%). From combinational analyses of these pharmacokinetic parameters, and of the results of the in-vitro absorption and metabolism experiments, we conclude that azalomycin F is absorbed relatively slowly and with difficulty by the intestinal tract, and subsequently can be rapidly distributed into the tissues and/or intracellular f of rats. Azalomycin F is stable in plasma, whole blood, and the liver, and presents plasma protein binding ratios of more than 90%. Moreover, one of the major elimination routes of azalomycin F is its excretion through bile and feces. Together, the above indicate that azalomycin F is suitable for administration by intravenous injection when used for systemic diseases, while, by oral administration, it can be used in the treatment of diseases of the gastrointestinal tract.

Highlights

Antimicrobial resistance has emerged as a serious threat to human health and economic development, and new antimicrobial agents are desperately need [1,2]
to reach Cmax (Tmax) and Cmax were, respectively, 3 h and 0.325 mg/L, after azalomycin F was administrated by gavage
The pharmacokinetics of azalomycin F were first investigated, and the plasma concentration time courses and pharmacokinetic parameters thereof, in rats, were obtained after azalomycin F was administrated by gavage (26.4 mg/kg) and intravenous injection (2.2 mg/kg)

Summary

Introduction

Antimicrobial resistance has emerged as a serious threat to human health and economic development, and new antimicrobial agents are desperately need [1,2]. Azalomycin F, a 36-membered polyhydroxy macrolide produced by many streptomycete strains [3,4,5,6], has various bioactivities against Gram-positive bacteria, yeast, fungi, and protozoa [3,6,7,8,9], and even some clinical studies on its anti-trichomoniasis and anti-candida infectious effects have been performed [3,10]. It presents remarkably inhibitory activity of the interleukin-1 receptor [11,12,13]. Based on chemical and genomic analyses, the absolute configurations of their analogs niphimycins were proposed in 2018 [15], and their absolute configurations were subsequently suggested in 2021 [16]

Methods

Results

Conclusion