Pharmacokinetics, bioavailability, and tissue disposal profiles of Tiamulin fumarate in Nile tilapia (Oreochromis niloticus) following oral and intravenous administrations

Abstract

Tiamulin fumarate (TIF) is a pleuromutilin antibiotic and has high activity against animal bacterial pathogens including aquatic bacterial pathogens. However, its pharmacokinetic profiles, tissue distribution characteristics and bioavailability in aquatic animals remain unknown. The objective of this study was to investigate the pharmacokinetics and tissue distribution regularities of TIF in tilapia (Oreochromis niloticus) following a single oral (PO) dose of 20 mg/kg body weight (bw) and a single intravenous (IV) dose of 5 mg/kg bw at 22 ± 1°C, respectively. TIF concentrations in tilapia plasma and tissues were determined using the isotope dilution HPLC‐HESI‐MS/MS procedure, which was validated according to the guidelines defined by US Food and Drug Administration. TIF was well distributed throughout the body compartments of tilapia judged by the apparent volume of distribution (Vd) >1 L/kg (6.69 L/kg PO and 1.78 L/kg IV). TIF had a short mean residence time (MRT; 22.82 h PO and 14.61 h IV) and quick total body clearance (CLb) (0.62 L kg−1 h−1 PO and 0.60 L kg−1 h−1 IV). The total area under the curve (AUCtot) of plasma were 32.25 μg h−1 ml−1 (PO) and 8.30 μg h−1 ml (IV), respectively, and the oral absolute bioavailability (F%) of TIF was calculated to be approximately 97.1%. For tissue distribution, high concentrations of TIF were found in kidney, and the longest MRT was recorded in bile. The withdrawal time (WT) of TIF in muscle, skin, liver, kidney, gill, and bile was 3.75 (4) and 1.79 (2), 1.77 (2) and 2.06 (3), 6.41 (7) and 1.97 (2), 6.95 (7) and 3.98 (4), 4.92 (5) and 2.36 (3), and 7.06 (8) and 6.16 (7) days after PO and IV administration, respectively. The present investigations indicated that TIF was quickly absorbed, well distributed, rapidly eliminated in tilapia, and it could serve as reference data for establishing use regimen and provide useful information for the further development of TIF in aquaculture.

Temperature-Dependent Residue Depletion Regularities of Tiamulin in Nile Tilapia (Oreochromis niloticus) Following Multiple Oral Administrations

“…Prior to the administration, the fish were anesthetized with bicarbonate-buffered (1:1) tricaine methanesulfonate (150 µg/L, MS-222) in order to calm the fish for about 30-60 s for drug administration (27,28). Fish in the experimental group were weighed and administrated with tiamulin solution at a dose of 20 mg/kg body weight by oral gavage directly to the stomach via the stomach tube (29).…”

A UPLC-MS/MS method for simultaneous determination of tiamulin and its metabolites in Crucian carp (Carassius carassius): an in vivo metabolism and tissue distribution study

“…Tiamulin (TML) is a semi-synthetic derivative of pleuromutilin, a naturally occurring diterpene antibiotic produced by the fungi Pleurotus mutilus and Clitopilus (Witkamp et al, 1996;Liu et al, 2021). It was discovered by Frederick Kavanagh in 1951 in the USA and was widely used after the 1960s (Kavanagh et al, 1951).…”

“…However, there are concerns about the pharmacokinetics and distribution of TML and its metabolites in pigs (Cambeiro-Peŕez et al, 2020), cattle (Kriukova et al, 2020), chickens (Garmyn et al, 2017), and other livestock. There are few TML pharmacokinetics (Liu et al, 2021) and residue depletion studies (Cuiyv et al, 2021) in fish. A recent report (Sun et al, 2017) showed significant metabolic differences in TML in various farm animals, which aroused our interest in TML metabolites in fish.…”