Pharmacokinetics/Pharmacodynamics of Acetaminophen Analgesia in Japanese Patients with Chronic Pain

Shinoda, Shigeo; Aoyama, T.; Aoyama, Yusuke; Tomioka, Sachiko; Matsumoto, Yoshiaki; Ohe, Yoko

doi:10.1248/bpb.30.157

Cited by 40 publications

(43 citation statements)

References 23 publications

(14 reference statements)

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“…At first, reference PBPK models for APAP and CAF were established by using clinical PK data ( Supplementary Figure S2, Supplementary Table S1‐S5 ) 8, 20, 21, 25. Twenty‐one biochemical processes were implemented in the PBPK models of CAF and APAP ( Figure 2) to represent key metabolic reactions, active drug transport ( Supplementary Table S2 ), as well as elimination processes ( Supplementary Table S4 ) 29, 30…”

Section: Resultsmentioning

confidence: 99%

“…PD responses of CAF and APAP were therefore predicted for an in vivo situation by the application of PICD14 thereby coupling in vitro toxicity data with drug‐specific PBPK models. To validate the PBPK models, simulated drug concentrations of APAP, CAF, and their main metabolites (APAPC, acetaminophen cysteine; APAPG, acetaminophen glucuronide; APAPS, acetaminophen sulfate; PX, paraxanthine; TP, theophylline; and TB, theobromine) were first assessed with clinical PK profiles from several studies obtained for different dosage regimens 8, 11, 20, 21, 22, 23, 24, 25, 26, 27. Using an additive PD response model, the influence of CAF on APAP‐induced hepatotoxicity was analyzed for key cellular processes and individual genes.…”

Section: Figurementioning

confidence: 99%

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Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Thiel

Cordes

Baier

et al. 2017

CPT Pharmacom & Syst Pharma

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Acetaminophen (APAP) is a widely used analgesic drug that is frequently co‐administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP‐induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co‐medication with CAF. Therefore, drug‐drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug‐specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP‐induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice.

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Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Thiel

Cordes

Baier

et al. 2017

CPT Pharmacom & Syst Pharma

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“…TRPA1 is a sensory receptor for oxidants and thiol-reactive electrophilic compounds 6-8, and APAP is metabolized in vivo to the highly reactive electrophilic compound NAPQI in humans and mice following therapeutic, non-toxic doses of APAP 19,24,26 . We, therefore, examined whether NAPQI can activate TRPA1 directly, using increases in [Ca mice, demonstrating that NAPQI excites cultured sensory neurons through activation of TRPA1 (Fig.…”

Section: The Antinociceptive Effect Of Apap Requires Trpa1mentioning

confidence: 99%

“…These early experiments and the subsequent findings that TRPA1 is activated by electrophilic compounds 4,5 led us to speculate that p-AP and APAP indirectly activate TRPA1 on primary sensory neurons, after their conversion to electrophilic compounds such as p-benzoquinone (p-BQ) and N-acetyl-p-benzoquinoneimine (NAPQI). The formation of these electrophilic compounds in vivo is catalysed by several enzymes, including cytochrome P450 (CYP450) monoxygenases, peroxidases and COX, many of which are present in the central nervous system [19][20][21][24][25][26][27][28][29] . NAPQI is believed to mediate the well-known hepato-and nephro-toxic effects of APAP.…”

mentioning

confidence: 99%

“…NAPQI is believed to mediate the well-known hepato-and nephro-toxic effects of APAP. However, NAPQI metabolites, including l-cysteinyl-S-APAP, can be detected in human and mouse blood or urine after ingestion of therapeutic and non-toxic doses of APAP 19,24,26 . The finding of CYP450 monoxygenase and COX-2 activity and immunoreactivity in the rat and human spinal cord, including laminae I and II of the dorsal horn 28,29 , is of particular interest and raises the possibility that NAPQI is formed in regions of the spinal cord where the central terminals of TRPA1-expressing neurons are abundant.…”

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confidence: 99%

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TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

et al. 2011

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TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1 − / − mice. The electrophilic metabolites N-acetylp-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-pbenzoquinoneimine metabolite l-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1 − / − mice. Intrathecal injection of a non-electrophilic cannabinoid, ∆ 9 -tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.

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Paracetamol (acetaminophen) for chronic non-cancer pain in children and adolescents

Cooper

Fisher

Anderson

et al. 2017

Cochrane Database of Systematic Reviews

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There was no evidence from randomised controlled trials to support or refute the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of paracetamol to treat chronic non-cancer pain in children and adolescents.We know from adult randomised controlled trials that paracetamol, can be effective, in certain doses, and in certain pain conditions (not always chronic).This means that no conclusions could be made about efficacy or harm in the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents.

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Pharmacokinetics/Pharmacodynamics of Acetaminophen Analgesia in Japanese Patients with Chronic Pain

Cited by 40 publications

References 23 publications

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

Paracetamol (acetaminophen) for chronic non-cancer pain in children and adolescents

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