title: Oxycodone recycling: a novel hypothesis of opioid tolerance development in humans.
abstract: We hypothesize that oxycodone (OC) recycling promotes sustained synaptic OC content, which prolongs OC's exposure to local μ-opioid receptors (μORs). In that way, OC recycling gives rise to OC tolerance in humans. To pilot test our hypothesis, we developed a whole-body OC mass transport tolerance recovery model. The model derived quantifiable measure of tolerance is TΩ. TΩ estimates OC's tolerance recovery in days; It is defined as the rate of recovery of OC's pharmacologic response after OC is stopped. We studied a random sample of five opioid intolerant healthy male subjects with no history of opioid or illicit drug use, or comorbidities in silico. Subjects were age 24.5 ± 2.3 yr (all values mean ± SD), weight 93 ± 20 kg, and CYP2D6 EM phenotype. Each subject was studied under two experimental conditions: (1) administration of a single oral dose of OC 12 ± 7 mg; and, after complete washout of OC from the intravascular pool, (2) administration of repetitive oral OC doses every 4h for 5 half-lives (t1/2 = 4.5h)-after which time steady-state was assumed. Repetitive OC dose TΩ fell 61% compared to single OC dose TΩ (5.2 ± 1.1 vs. 3.5 ± 0.7 days, p = 0.001). The fall in TΩ was associated with a significant 3-fold increase in extravascular OC content, which was accompanied by 2-fold increase in OC spillover from the extravascular pool, into the intravascular pool. Thus, the model predicted that a single dose of orally administered OC could give rise to tolerance. This is consistent with the widely held view of acute opioid tolerance. In addition, the dynamic changes accompanying repetitive OC dosing suggested that local unbound OC gave rise to both higher extravascular OC content and increased OC spillover. This reflects that OC stimulated endocytosis of μORs was accompanied by a reduction in the availability OC responsive neuroeffector cell surface μOR binding sites. We conclude that our hypothesis extends current concepts of opioid tolerance development to include OC recycling. OC recycling is a novel hypothesis of OC tolerance development in humans.
authors.affiliation: Plymouth Pharmacokinetic Modeling Study Group, Plymouth, MI, USA. Electronic address: OALinaresMD@gmail.com.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Linares
authors.affiliation: University of Connecticut, School of Pharmacy, Storrs, CT, USA; Western New England University, College of Pharmacy, Springfield, MA, USA; State University of New York at Buffalo College of Pharmacy, Buffalo, NY, USA; Pain and Palliative Care Pharmacy Residency, Stratton VA Medical Center, Albany, NY, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fudin
authors.affiliation: Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Schiesser
authors.affiliation: Wayne State University Law School, 471 W Palmer Ave., Detroit, MI, USA; Grace Hospice of Ann Arbor, 2755 Carpenter Rd., Ann Arbor, MI, USA.
authors.forename: Annemarie Daly
authors.initials: AD
authors.lastname: Linares
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, 3600 Market Street, Philadelphia, PA, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Boston
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D001692:Biological Transport; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004361:Drug Tolerance; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008297:Male; D009293:Opioid-Related Disorders / Q000503:physiopathology; D010098:Oxycodone / Q000493:pharmacokinetics*; D010641:Phenotype; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D010098:Oxycodone; D019389:Cytochrome P-450 CYP2D6