Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates

Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB 1 receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB 1 receptor agonist, completely prevents the analgesic ac- 250CNS Drug Reviews Vol. 12, No. 3-4, pp. 250-275 © 2006 tivity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB 1 agonists are being introduced for pain treatment, it comes out that an indirect cannabinomimetic had been extensively used (and sometimes overused) for more than a century.

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“…The mean elimination half-life is increased in premature infants (11 h), while it is 4 to 5 h in newborns (95,217).…”

Section: Hepatic Enzyme In-a Bertolini Et Almentioning

confidence: 99%

Paracetamol: New Vistas of an Old Drug

et al. 2006

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“…There are also models that are specifically geared towards optimal paracetamol dosing within the first few months of life. These models were typically developed using pooled data from multiple studies in, for example, preterm neonates, term neonates and infants [7,[11][12][13][14][15][16]. Timedependent changes in growth and maturation are frequently expressed in different time scales using, for example, post-conceptional age (PCA), post-menstrual age (PMA), gestational age (GA) or post-natal age (PNA) [17].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds

Somani

Thelen

Zheng

et al. 2015

Brit J Clinical Pharma

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AIMSEvidence suggests that the rate of oral drug absorption changes during early childhood. Yet, respective clinical implications are currently unclear, particularly for preterm neonates. The objective of this study was to evaluate changes in oral drug absorption after birth for different Biopharmaceutics Classification System (BCS) class I and II compounds to better understand respective implications for paediatric pharmacotherapy. METHODSTwo paradigm compounds were selected for BCS class I (paracetamol (acetaminophen) and theophylline) and II (indomethacin and ibuprofen), respectively, based on the availability of clinical literature data following intravenous and oral dosing. A comparative population pharmacokinetic analysis was performed in a step-wise manner in NONMEM® 7.2 to characterize and predict changes in oral drug absorption after birth for paracetamol, theophylline and indomethacin. RESULTSA one compartment model with an age-dependent maturation function for oral drug absorption was found appropriate to characterize the pharmacokinetics of paracetamol. Our findings indicate that the rate at which a drug is absorbed from the GI tract reaches adult levels within about 1 week after birth. The maturation function for paracetamol was found applicable to theophylline and indomethacin once solubility limitations were overcome via drug formulation. The influence of excipients on solubility and, hence, oral bioavailability was confirmed for ibuprofen, a second BCS class II compound. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Preterm birth is associated with high morbidity and mortality resulting in a high demand for drug therapy.• Clinical evidence suggests that the oral absorption process of a drug undergoes substantial changes after birth. The impact of these physiological changes on oral drug therapy is currently unclear. WHAT THIS STUDY ADDS• This study improves our understanding of changes in oral drug absorption in preterm neonates for two drugs from both BCS class I and BCS class II.• Our findings indicate that these changes in oral absorption within the first few days after birth are a system-specific property, which can be used to guide oral dosing of BCS class I and BCS class II compounds in preterm neonates.

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“…Clearance is lowest in neonates, with values rising through childhood. Elimination half-life is 2-4 h in normal adults, increasing to 4-5 h in newborns and to 11 h in premature infants [15,16]. One to four percent is excreted unchanged in the urine, and an increased dose interval of 6-8 h is recommended in patients with severe renal impairment (GFR less than 10 ml.min )1 ) [17,18].…”

Section: Pharmacokineticsmentioning

confidence: 99%