FACTORS THAT INFLUENCE PHARMACOKINETIC PROFILES OF THERAPEUTIC DRUGS

2.1 Absorption

2.1.1 Oral drug absorption in herbivores and folivores

Many Australian mammals are primarily herbivores and folivory is common. For example, the eastern ring­tailed possum, koala and greater glider (Petauroides volans) are obligate folivores (Foley and Moore 2005).

The koala, one of the most studied specialist foli- vores, is thought to possess a variety of physiological defences that limit oral absorption of PSMs and enhance their elimination once absorbed. Factors that may limit PSM absorption from the koala gut lumen include: binding to, or entrapment by, the ever-present fibrous ingesta, as has been reported in the horse (a generalist herbivore) (Baggot 1992); some metabolism by normal gut microbes (Freeland and Janzen 1974); rapid small intestinal transit (particulate matter transits the small intestine in ~6 min, soluble material within 60 min) (Cork and Warner 1983); and possible existence of a high density of efficient transporter molecules (or cel­lular efflux pumps) on enterocyte membranes that pump PSMs and xenobiotics back into the gut lumen (Sorensen and Dearing 2006). The existence of such efflux pumps has not been reported in Australian herbi­vores or folivores, because of the lack of studies

Table 11.1. Summaryofselected pharmacological studies undertaken in Australian mammals

For recommended drug dosages see Appendix 4.

11 - Pharmacology

Table 11.1. (continued)

172 CurrentTherapyin MedicineofAustraIian Mammals

Table 11.1.

174 CurrentTherapyin MedicineofAustraIian Mammals

¹Barbosa etal. 2015; ²Boonstra etal. 2015; ³Meegan etal. 2013; ⁴Scott etal. 2020; ⁵Garaa-Parraga etal. 2010; ⁶Simeone etal. 2014; ⁷Le-Bert 2023; ⁸Garda-Parraga etal. 2016

investigating their presence. Cellular efflux pumps have been identified in many species, including humans (Thiebaut et al. 1987) and dogs (Allenspach et al. 2006), and an increased density of efflux pumps along the GIT mucosa has been identified in the horse (Tyden et al. 2009). Poor oral absorption of enrofloxacin and meloxicam has been reported in the koala (Griffith et al. 2010; Kimble et al. 2013a). In contrast, the antifungal drug posaconazole when administered orally has a median bioavailability of 66% in clinically normal koalas (Gharibi et al. 2017) compared with an average bioavailability of 26% in dogs (Kendall and Papich 2015). This bioavailability has been attributed to the fact that the drug is highly lipophilic in acidic environments (the pH of the koala forestomach is 2.7 ± 0.1 and hinds­tomach is 1.9 ± 0.2 [Cork et al. 1983]) and thus more readily crosses the intestinal cell membranes to enter the circulation (Gharibi et al. 2017) compared with higher pH environments. Oral paracetamol at 15 mg/kg has similar absorption as a SC injection at the same dose in the koala (Govendir et. al. 2024).

Scheelings et al. (2015) reported that enrofloxacin administered at 10 mg/kg SC to eastern ring-tailed pos­sums was likely ineffective, whereas oral administration of this dosage resulted in higher plasma concentrations. Although not explicitly stated by the authors, enrofloxa- cin undergoes some faecal elimination and as the eastern ring-tailed possum ingests caecotrophs, this may contrib­ute to higher enrofloxacin plasma concentrations when administered PO versus SC.

2.1.2 Subcutaneous absorption

Absorption of SC injected drugs is reduced in some Aus­tralian marsupials. For example, enrofloxacin has a SC bioavailability of ~35% in the koala (Griffith et al. 2010; Black et al. 2014b) compared with 77% in rabbits (Broome et al. 1991) and >90% in alpacas (Gandolf et al. 2005). Equally, SC bioavailability of meloxicam in the koala is reduced compared with other species (Kimble et al. 2013a). The reasons for this have not yet been determined.

2.2 Distribution

2.2.1 Plasma protein binding

Although most drugs circulate with a proportion bound to plasma proteins, the ratio of unbound to bound drug may not be constant between species. The proportion of plasma protein binding may require incorporation into dosage calculations because the unbound drug is con­sidered therapeutically active and the bound fraction acts as a reservoir from which the drug dissociates to maintain the unbound to bound equilibrium (Lindup and Orme 1981). The plasma protein binding of enro- floxacin is 34.74 ± 2.33% in dogs (Bidgood and Papich 2005) versus 55.4 ± 1.9% in the koala (Griffith et al. 2010) and is unlikely to be associated with significant interspecies clinical PK effects. However, this is not the case with cefovecin (Convenia_®, Zoetis, West Ryde, NSW, Australia). The PK profile of cefovecin is charac­terised by a long elimination half-life of 5.5 and 7 d in dogs and cats, respectively, and is attributed to high plasma protein binding of ≥96% in both species (Stege- mann et al. 2006). Tubular reabsorption in the kidneys may also occur in dogs and cats, further contributing to the long half-life of cefovecin (Stegemann et al. 2006). Long elimination half-life times for cefovecin have been reported as 3.5 and 8.5 d in a neonate and adult common bottle-nosed dolphin (Tursiops truncates), respectively (Garcia-Parraga et al. 2010), and an elimination half­life of ~4 wk in Patagonian sea-lions (Otaria flavescens) (Garcia-Parraga et al. 2010; Garcia-Parraga et al. 2016) (see Table 11.2). However, in vitro studies of cefovecin binding to plasma proteins of the koala, common brush-tailed possum, eastern ring-tailed possum, red kangaroo (Osphranter rufus), eastern grey kangaroo (Macropus giganteus) and Tasmanian devil demon­strated the proportion of binding between 12% and 40% (Gharibi 2018), suggesting that the elimination half-life of cefovecin in these species is likely to be con­siderably shorter than in the dog and cat. Cefovecin at 8 mg/kg SC as a single bolus was administered to six koalas and serial blood samples were collected over 96 hr. Cefovecin plasma concentrations at all time points in all animals were II metabolism is characterised by the addition of a glucuronyl, sulfate, methyl, acetyl or glycyl moiety to either the parent molecule or the phase I metabolite, via transaminases such as uridine diphosphate-glucurono- syltransferases and sulfotransferases (Di 2014). Glucuro­nidation is an important pathway for the excretion of phenolic PSMs in koalas (McLean et al. 2003). Thus, in those folivore marsupials that have been studied, there are both phase I (oxidative) and phase II (conjugative) metabolic reactions, which target different dietary PSMs (McLean et al. 2003) and these different biotransforma­tion pathways can, likewise, target specific drugs.

Differences in the activity of metabolism pathways in the koala, eastern ring-tailed possum, common brush­tailed possum, rats and dogs can be important in recog­nising the implication for some drug dosages. The three marsupial species appear to have active phase I oxidative pathways to detoxify relatively high concentrations of PSMs such as terpenoids and any xenobiotic that also undergoes metabolism by phase I oxidation. Conse­quently, the popular NSAID, meloxicam, is eliminated rapidly in these species (Kimble et al. 2013a; Kimble et al. 2014) as shown in Fig. 11.1. The half-life of meloxicam in koalas is 1.19 hr (range 0.71-1.62 hr) (Kimble et al. 2013a), 24 hr in dogs (Busch et al. 1998) and ~13 hr in humans (Turck et al. 1996). There is currently limited information on the rate of metabolism of other NSAIDs by these mar­supials, but Kimble (2015) demonstrated that the NSAIDs diclofenac and flurbiprofen are also rapidly metabolised by the koala and the common brush-tailed and eastern ring-tailed possums. An in vitro study using hepatic enzymes from the common brush-tailed possum, eastern ring-tailed possum and koala showed these species deplete the NSAID carprofen by phase I and phase II metabolism significantly faster compared with depletion by hepatic enzymes from rats, cats and dogs (Lillo 2020), suggesting that carprofen may also have a faster clearance in these marsupial species compared with eutherian species.

Fig. 11.1. Rate of in vitro meloxicam depletion concentration (expressed as log substrate remaining) versus incubation time. The rate of depletion of meloxicam (steeper gradient) is faster in the common brush-tailed possum (Trichosurus vulpecula), followed by the koala (Phascolarctos cinereus), the eastern ring-tailed possum (Pseudocheirusperegrinus) and then the rat (modified from Kimble et al. 2014).

Differences in metabolism pathways among the spe­cies may result in variability in the structure or quantity of metabolites generated. For example, ciprofloxacin is an active metabolite of enrofloxacin in many species, with both enrofloxacin and ciprofloxacin responsible for anti­microbial activity in vivo (Lautzenhiser et al. 2001). When 5 mg/kg of enrofloxacin was administered PO to dogs, the maximal plasma concentration of ciprofloxacin mean (± SD) was 0.36 ± 0.10 μg∕mL, 3 hr after administration (Bidgood and Papich 2005); whereas a 10 mg/kg IV enro- floxacin bolus administered to six koalas resulted in maximal ciprofloxacin concentrations of 0.13-0.25 μg/ mL in the plasma of half of the koalas at 2 min but was below 0.13 μg∕mL by 15 min (Black et al. 2014b). Low cip­rofloxacin concentrations after enrofloxacin administra­tion have been reported in chickens (Knoll et al. 1999), foals (Bermingham et al. 2000) and pigs (Nielsen and Gyrd-Hansen 1997) and may be caused by either reduced biotransformation of enrofloxacin to ciprofloxacin or rapid elimination of ciprofloxacin. Additionally, when dosed with amoxicillin, koalas rapidly transform this antibiotic to a glucuronide-like metabolite that has not been reported in any other species (Kimble et al. 2020).

The common brush-tailed possum appears relatively resistant to ingested toxins (McDowell and McLeod 2007).

This species can tolerate higher doses of some anthelmin­tics (Ralston et al. 2001) and paracetamol (Eason et al. 1999), which may be attributable to its rapid metabolism pathways. Some of these pathways also appear to undergo adaptation to deal with higher toxin concentrations encountered in the diet. This species and other indigenous marsupials in WA have developed tolerance to sodium fluoroacetate (1080 toxin) (King et al. 1978) and the terpe­noid 1,8-cineole (McLean and Foley 1997).

2.4 Excretion

Excretion is the PK process whereby water-soluble mole­cules or metabolites are eliminated from the body unmodified, primarily by the kidney. Some species that live in either semi-arid or arid environments are able to withstand long periods of drought by conserving body water and this adaptation delays excretion of some xeno- biotics. The renal plasma flow, glomerular filtration rate (GFR) and urine flow rates of the red kangaroo and common wallaroo (O. robustus), when in either the hydrated or dehydrated state, are much lower than those of similarly sized eutherians (Dawson and Denny 1969; Dawson and Hulbert 1970; Bradshaw et al. 2001). Roths­child’s rock-wallaby (Petrogale rothschildi) is also reported to have a low GFR and renal blood flow, but no significant difference in tubular function (Bradshaw et al. 2001). Similarly, the common brush-tailed possum also has low GFR and renal plasma flow (Reid and McDonald 1968). The spectacled hare-wallaby (Lagorchestes conspicillatus) conserves water by producing a highly concentrated urine because the renal tubules are highly responsive to lysine vasopressin and antidiuretic hormone (Bradshaw et al. 2001). Most xenobiotics are too large to be filtered by glo­meruli and rely on tubular secretion for elimination. Studies focusing specifically on xenobiotic excretion in Australian mammals have yet to be performed.

3.