Propacetamol in dogs: First description of its pharmacokinetics after intravenous and oral administration

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Highlights

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    Plasma concentrations of APAP were lower than those of its inactive metabolites.

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    The IV propacetamol administration produced 30% more APAP then the oral administration.

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    30 mg/kg propacetamol dose produced APAP concentration below the threshold sufficient to provide analgesia in adult humans.

Abstract

Propacetamol is a prodrug form of paracetamol (APAP) licensed for human use as a pain reliever in postoperative care. It is prescribed if APAP cannot be administered orally or rectally to a patient and for patients in whom nonsteroidal anti-inflammatory drugs are contraindicated. In this study, we aimed to quantify the pharmacokinetics of APAP and its metabolites, paracetamol sulfate (PS), paracetamol glucuronide (PG), and N-acetyl-p-benzoquinone imine (NAPQI), after a single oral and intravenous (IV) administration of 30 mg/kg of propacetamol to six healthy adult Labrador dogs according to a 2 × 2 crossover study. The analyses were performed using a validated HPLC-MS/MS method.

PS and PG exposures were higher than that of APAP, while NAPQI concentrations were constantly below the detection limit of the analytical method. IV propacetamol administration produced 30% more APAP than oral administration. However, propacetamol released a significantly lower amount of active moiety in dogs than in humans. The propacetamol dose administered in this study did not produce plasma APAP concentrations above the threshold sufficient to provide analgesia in adult humans (4 μg/mL). In conclusion, direct IV injection of APAP instead of propacetamol might be a better clinical option for pain relief in dogs.

Introduction

Pain is commonly experienced after surgical procedures, and multiple medications (e.g., painkillers) are routinely used to control pain. The drug armamentarium in veterinary medicine is little and sometimes obsolete compared to that in humans (Giorgi, 2012). Human drugs are used off-label in animal species without specific studies in the target animals, leading to a lack of efficacy or worse toxicity (Giorgi et al., 2009). In the last two decades, the use of paracetamol (APAP) as a painkiller in humans has been reestablished, and consequently, its interest has increased in the veterinary field as well. Currently, several pharmacokinetic and pharmacodynamic features of APAP are known in dogs (KuKanich, 2010; Neirinckx et al., 2010; Serrano-Rodríguez et al., 2019; Sartini et al., 2021; Fadel et al., 2021); however, no information is available concerning its prodrug propacetamol in canine species.

Propacetamol is a prodrug form of APAP (N,N′-diethylglycine ester) formed by the esterification of APAP and the carboxylic acid diethylglycine (Fig. 1). It has the advantage of being more water-soluble. Propacetamol is used in postoperative care and delivered via intravenous (IV) route (Binhas et al., 2004). It is prescribed if APAP cannot be administered orally or rectally to a patient and for patients in whom nonsteroidal anti-inflammatory drugs are contraindicated. The onset of analgesia from propacetamol is more rapid than that from APAP administered orally or rectally (Moller et al., 2005a, Moller et al., 2005b). As a bioprecursor, propacetamol is not therapeutically active, and its effectiveness depends on the amount of APAP formed. It has been reported that 2 g of propacetamol is equivalent to 1 g of APAP in humans (Flouvat et al., 2004).

The aim of the present study was to evaluate the pharmacokinetics of propacetamol in terms of APAP and its main metabolites, paracetamol sulfate (PS), paracetamol glucuronide (PG), and N-acetyl-p-benzoquinone imine (NAPQI), in Labrador dogs after IV and oral (PO) administration.

Section snippets

Drugs and chemicals

APAP, PS, PG, and NAPQI standards for the analytical test (purity ≥99%) and the internal standard (IS), 4-acetamidophenyl β-D-glucuronide-d3 sodium salt (purity ≥99%), were provided by Merk (Poznań, Poland). Acetonitrile and methanol were purchased from Avantor Performance Materials Poland (Gliwice, Poland). Formic acid (99%) was purchased from VWR Chemicals (Randor, USA). Milli-Q grade water was purified using a Milli-Q UV purification system (Millipore Corporation, Poznań, Poland).

Animals and experimental design

Six adult

Validation

Validation of the method showed high accuracy and precision with good linearity (R2 > 0.99). No interfering peaks from endogenous compounds were observed in the retention times of the target analytes in canine plasma samples. Satisfactory recoveries for all analytes were obtained (APAP, 91.3 ± 3.9%; PS, 104.2 ± 4.8%; PG, 94.6 ± 3.9%; NAPQI, 89.6 ± 4.3%). The results of CVs for repeatability were 8.8 ± 2.3, 10.1 ± 3.6, 13.6 ± 4.4, and 12.9 ± 3.2% for APAP, PS, PG, and NAPQI, respectively. The

Discussion

Propacetamol is the most commonly prescribed drug in infants and neonates to treat mild to moderate pain or supplement opioid analgesia (Barr et al., 2002; Allegaert et al., 2003, Allegaert et al., 2004). Its use in this pediatric age group is justified because IV administration reduces the plasma concentration variability of APAP owing to the erratic absorption via the rectal and oral routes (Prins et al., 2008). This is the first time that propacetamol has been tested in an animal species of

Declaration of Competing Interest

None.

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