Pharmacokinetic aspects of meloxicam in koalas: including its hepatic microsomal metabolism compared with other selected species
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Open Access
Type
ThesisThesis type
Doctor of PhilosophyAuthor/s
Kimble, BenjaminAbstract
Prior to this research, no disposition studies of meloxicam (nor any other non steroidal anti-inflammatory drugs) had been conducted in koalas (a specialist Eucalyptus spp. foliage feeder) despite being readily administered to this species, in the field. Thus, aspects of the in-vivo ...
See morePrior to this research, no disposition studies of meloxicam (nor any other non steroidal anti-inflammatory drugs) had been conducted in koalas (a specialist Eucalyptus spp. foliage feeder) despite being readily administered to this species, in the field. Thus, aspects of the in-vivo pharmacokinetic profile of meloxicam in the koala and the in-vitro metabolism of meloxicam in the koala and selected species were investigated. In the first stage of the research, a simple, sensitive and improved method using high performance liquid chromatography equipped with photo diode array detection was developed and validated to determine meloxicam concentrations in koala plasma, applicable for in-vivo pharmacokinetic study. Following intravenous injection, meloxicam exhibited a rapid plasma clearance of 0.44 ± 0.20 L/h/kg in koalas (n = 5). Median plasma terminal elimination t1/2 was 1.19 h (range 0.71 to 1.62 h). In koalas, bioavailability after the subcutaneous injection was approximately 56 to 70 % where oral bioavailability was negligible. Plasma protein binding of meloxicam was about 98%. Three hydroxylated metabolites of meloxicam (M1, M2 and M3) were detected in the koala plasma with one (M1) identified as the 5-hydroxy methyl metabolite. According to the in-vitro hepatic microsomal metabolism of meloxicam, it was demonstrated that biotransformation of meloxicam, likely mediated via cytochrome P450 enzymes, were much faster in koalas (and also in other Eucalyptus spp. foliage feeders: ringtail possums and brushtail possums) compared to rats or dogs. The rank order of apparent in-vitro intrinsic clearance was brushtail possums (n = 3) (mean: 394 μL/min/mg protein) > koalas (n = 6) (50 μL/min/mg protein) > ringtail possums (n = 2) (36 μL/min/mg protein) (with no significant difference between koalas and ringtail possums) > pooled rats (3.2 μL/min/mg protein) > pooled dogs (not determined as the rate of metabolism was too slow). According to the in-vitro study, single hydroxylated metabolite (M1) was determined as the major product of meloxicam in brushtail possums and the rat whereas multiple hydroxylated metabolites were observed in the koala (M1, M2, and M3) and the ringtail possum (M1 and M3). Using a well-stirred model, this research showed applicability of predicting in-vivo clearance of meloxicam in koalas and the rat from the apparent in-vitro intrinsic clearance data (average fold error for prediction was less than 2). While cytochrome P4502C9 is the major responsible enzymes for metabolism of meloxicam, the research also found that the stability of other cytochrome P4502C9 substrates, particularly non steroidal anti-inflammatory drugs were also generally not stable in hepatic microsomes of koala and other Eucalyptus.spp foliage feeders than the rat. Particularly, there was some similarity on the pattern of CYP2C9 substrates stabilities between koala and ringtail possum (Eucalyptus spp. foliage specialist feeders). This research demonstrated that koalas exhibited rapid plasma clearance and extremely poor oral bioavailability of meloxicam compared with other eutherian species. Due to differences in the rate of hepatic metabolism on meloxicam, other eutherians such as rats or dogs are inadequate model for dosage extrapolation of this drug in koalas. Furthermore, as catalytic activity of cytochrome P4502C-like enzymes appeared to be different in these Eucalyptus spp. foliage feeders, it is highly recommended to consider when extrapolating dosage of therapeutic drugs (cytochrome P4502C9 substrates), particularly non steroidal anti-inflammatory drugs, from other eutherians. On the other hand, as in-vivo clearance is one of the pharmacokinetic indexes for determining the dosage of drug, this study demonstrates the utility of in-vitro to in-vivo scaling as an alternative prediction method of drug clearance in koalas.
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See morePrior to this research, no disposition studies of meloxicam (nor any other non steroidal anti-inflammatory drugs) had been conducted in koalas (a specialist Eucalyptus spp. foliage feeder) despite being readily administered to this species, in the field. Thus, aspects of the in-vivo pharmacokinetic profile of meloxicam in the koala and the in-vitro metabolism of meloxicam in the koala and selected species were investigated. In the first stage of the research, a simple, sensitive and improved method using high performance liquid chromatography equipped with photo diode array detection was developed and validated to determine meloxicam concentrations in koala plasma, applicable for in-vivo pharmacokinetic study. Following intravenous injection, meloxicam exhibited a rapid plasma clearance of 0.44 ± 0.20 L/h/kg in koalas (n = 5). Median plasma terminal elimination t1/2 was 1.19 h (range 0.71 to 1.62 h). In koalas, bioavailability after the subcutaneous injection was approximately 56 to 70 % where oral bioavailability was negligible. Plasma protein binding of meloxicam was about 98%. Three hydroxylated metabolites of meloxicam (M1, M2 and M3) were detected in the koala plasma with one (M1) identified as the 5-hydroxy methyl metabolite. According to the in-vitro hepatic microsomal metabolism of meloxicam, it was demonstrated that biotransformation of meloxicam, likely mediated via cytochrome P450 enzymes, were much faster in koalas (and also in other Eucalyptus spp. foliage feeders: ringtail possums and brushtail possums) compared to rats or dogs. The rank order of apparent in-vitro intrinsic clearance was brushtail possums (n = 3) (mean: 394 μL/min/mg protein) > koalas (n = 6) (50 μL/min/mg protein) > ringtail possums (n = 2) (36 μL/min/mg protein) (with no significant difference between koalas and ringtail possums) > pooled rats (3.2 μL/min/mg protein) > pooled dogs (not determined as the rate of metabolism was too slow). According to the in-vitro study, single hydroxylated metabolite (M1) was determined as the major product of meloxicam in brushtail possums and the rat whereas multiple hydroxylated metabolites were observed in the koala (M1, M2, and M3) and the ringtail possum (M1 and M3). Using a well-stirred model, this research showed applicability of predicting in-vivo clearance of meloxicam in koalas and the rat from the apparent in-vitro intrinsic clearance data (average fold error for prediction was less than 2). While cytochrome P4502C9 is the major responsible enzymes for metabolism of meloxicam, the research also found that the stability of other cytochrome P4502C9 substrates, particularly non steroidal anti-inflammatory drugs were also generally not stable in hepatic microsomes of koala and other Eucalyptus.spp foliage feeders than the rat. Particularly, there was some similarity on the pattern of CYP2C9 substrates stabilities between koala and ringtail possum (Eucalyptus spp. foliage specialist feeders). This research demonstrated that koalas exhibited rapid plasma clearance and extremely poor oral bioavailability of meloxicam compared with other eutherian species. Due to differences in the rate of hepatic metabolism on meloxicam, other eutherians such as rats or dogs are inadequate model for dosage extrapolation of this drug in koalas. Furthermore, as catalytic activity of cytochrome P4502C-like enzymes appeared to be different in these Eucalyptus spp. foliage feeders, it is highly recommended to consider when extrapolating dosage of therapeutic drugs (cytochrome P4502C9 substrates), particularly non steroidal anti-inflammatory drugs, from other eutherians. On the other hand, as in-vivo clearance is one of the pharmacokinetic indexes for determining the dosage of drug, this study demonstrates the utility of in-vitro to in-vivo scaling as an alternative prediction method of drug clearance in koalas.
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Date
2015-06-05Faculty/School
Faculty of Veterinary ScienceAwarding institution
The University of SydneyShare