ArticleBritish journal of pharmacology2007
Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux.
Article in British journal of pharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 63 citations in OpenAlex.
- Reliability of in vitro data for the mechanistic prediction of brain extracellular fluid pharmacokinetics of P-glycoprotein substrates in vivo; are we scaling correctly?Journal of pharmacokinetics and pharmacodynamics · 2025Article
- Do P-glycoprotein-mediated drug-drug interactions at the blood-brain barrier impact morphine brain distribution?Journal of pharmacokinetics and pharmacodynamics · 2025Article
- TET1-Lipid Nanoparticle Encapsulating Morphine for Specific Targeting of Peripheral Nerve for Pain Alleviation.International journal of nanomedicine · 2024Article
- Morphine Accumulates in the Retina Following Chronic Systemic Administration.Pharmaceuticals (Basel, Switzerland) · 2022Article
- In Vitro to In Vivo Extrapolation Linked to Physiologically Based Pharmacokinetic Models for Assessing the Brain Drug Disposition.The AAPS journal · 2022Review
- Pharmacokinetic modeling of morphine and its glucuronides: Comparison of nebulization versus intravenous route in healthy volunteers.CPT: pharmacometrics & systems pharmacology · 2022Article
- Blood-Placental Barrier Transfers and Pharmacokinetics of Unbound Morphine in Pregnant Rats with Multiple Microdialysis Systems.ACS pharmacology & translational science · 2021Article
- Blood-brain barrier: mechanisms governing permeability and interaction with peripherally acting μ-opioid receptor antagonists.Regional anesthesia and pain medicine · 2020Article
- The 3D Brain Unit Network Model to Study Spatial Brain Drug Exposure under Healthy and Pathological Conditions.Pharmaceutical research · 2020Article
- Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- Opioids and the Blood-Brain Barrier: A Dynamic Interaction with Consequences on Drug Disposition in Brain.Current neuropharmacology · 2017Review
- Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.CPT: pharmacometrics & systems pharmacology · 2017Article
- A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.Pharmaceutical research · 2017Article
- [Drug interactions in pain therapy].Schmerz (Berlin, Germany) · 2015Review
- Kinetics of drug action in disease states: towards physiology-based pharmacodynamic (PBPD) models.Journal of pharmacokinetics and pharmacodynamics · 2015Article
- Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions.Pharmaceutical research · 2015Review
- Challenges of using in vitro data for modeling P-glycoprotein efflux in the blood-brain barrier.Pharmaceutical research · 2014Review
- P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac.PloS one · 2014Article
- Enhanced analgesic responses after preferential delivery of morphine and fentanyl to the olfactory epithelium in rats.Anesthesia and analgesia · 2011Article
- Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance.Current topics in medicinal chemistry · 2011Review
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeBiophase equilibration must be considered to gain insight into the mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) correlations of opioids. The objective was to characterise in a quantitative manner the non-linear distribution kinetics of morphine in brain. EXPERIMENTAL APPROACH: Male rats received a 10-min infusion of 4 mg kg(-1) of morphine, combined with a continuous infusion of the P-glycoprotein (Pgp) inhibitor GF120918 or vehicle, or 40 mg kg(-1) morphine alone. Unbound extracellular fluid (ECF) concentrations obtained by intracerebral microdialysis and total blood concentrations were analysed using a population modelling approach. KEY
resultsBlood pharmacokinetics of morphine was best described with a three-compartment model and was not influenced by GF120918. Non-linear distribution kinetics in brain ECF was observed with increasing dose. A one compartment distribution model was developed, with separate expressions for passive diffusion, active saturable influx and active efflux by Pgp. The passive diffusion rate constant was 0.0014 min(-1). The active efflux rate constant decreased from 0.0195 min(-1) to 0.0113 min(-1) in the presence of GF120918. The active influx was insensitive to GF120918 and had a maximum transport (N(max)/V(ecf)) of 0.66 ng min(-1) ml(-1) and was saturated at low concentrations of morphine (C(50)=9.9 ng ml(-1)). CONCLUSIONS AND IMPLICATIONS: Brain distribution of morphine is determined by three factors: limited passive diffusion; active efflux, reduced by 42% by Pgp inhibition; low capacity active uptake. This implies blood concentration-dependency and sensitivity to drug-drug interactions. These factors should be taken into account in further investigations on PK-PD correlations of morphine.
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