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The Analysis of Pethidine Pharmacokinetics in Newborn Saliva, Plasma, and Brain Extracellular Fluid After Prenatal Intrauterine Exposure from Pregnant Mothers Receiving Intramuscular Dose Using PBPK Modeling

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Abstract

Background and Objective

Pethidine (meperidine) can decrease labor pain-associated mother’s hyperventilation and high cortisol-induced newborn complications. However, prenatal transplacentally acquired pethidine can cause side effects in newborns. High pethidine concentrations in the newborn brain extracellular fluid (bECF) can cause a serotonin crisis. Therapeutic drug monitoring (TDM) in newborns' blood distresses them and increases infection incidence, which can be overcome by using salivary TDM. Physiologically based pharmacokinetic (PBPK) modeling can predict drug concentrations in newborn plasma, saliva, and bECF after intrauterine pethidine exposure.

Methods

A healthy adult PBPK model was constructed, verified, and scaled to newborn and pregnant populations after intravenous and intramuscular pethidine administration. The pregnancy PBPK model was used to predict the newborn dose received transplacentally at birth, which was used as input to the newborn PBPK model to predict newborn plasma, saliva, and bECF pethidine concentrations and set correlation equations between them.

Results

Pethidine can be classified as a Salivary Excretion Classification System class II drug. The developed PBPK model predicted that, after maternal pethidine intramuscular doses of 100 mg and 150 mg, the newborn plasma and bECF concentrations were below the toxicity thresholds. Moreover, it was estimated that newborn saliva concentrations of 4.7 µM, 11.4 µM, and 57.7 µM can be used as salivary threshold concentrations for pethidine analgesic effects, side effects, and the risk for serotonin crisis, respectively, in newborns.

Conclusion

It was shown that saliva can be used for pethidine TDM in newborns during the first few days after delivery to mothers receiving pethidine.

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Acknowledgements

The authors acknowledge Jordan University of Science and Technology (Irbid, Jordan) and the University of Petra (Amman, Jordan) for all the facilities and support provided.

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  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan

    Mo’tasem M. Alsmadi

  2. Nanotechnology Institute, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan

    Mo’tasem M. Alsmadi

  3. College of Pharmacy, University of Petra, Amman, Jordan

    Nasir Idkaidek

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MMA had substantial contributions to the conception and design of the work; the acquisition, analysis, and interpretation of data, and the drafting of the work. MMA and NI were involved in revising the work critically for important intellectual content. All authors provided final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

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Alsmadi, M.M., Idkaidek, N. The Analysis of Pethidine Pharmacokinetics in Newborn Saliva, Plasma, and Brain Extracellular Fluid After Prenatal Intrauterine Exposure from Pregnant Mothers Receiving Intramuscular Dose Using PBPK Modeling. Eur J Drug Metab Pharmacokinet 48, 281–300 (2023). https://doi.org/10.1007/s13318-023-00823-x

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