title: Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model.
abstract: Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another.
  
  
  
  Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant.
  
  
  
  DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: -4.9; 95% confidence interval [CI]: -8.8 to -0.9) as well as a decreased Cl/F (MD: -4.0; 95% CI: -8.9 to -0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1-1330.6), CMAX (MD: 6.8; 95% CI: 2.7-10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5-35.6), as well as a decreased Cl/F (MD: -7.0; 95% CI: -11.6 to -2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4-1065.4), CMAX (MD: 5.3; 95% CI: 3.2-10.3), and T1/2 (MD: 18.3; 95% CI: 2.8-33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: -779.9; 95% CI: -1229.8 to -330), CMAX (MD: -6.1; 95% CI: -11.4 to -0.9), and T1/2 (MD: -19; 95% CI: -35.1 to -2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3-10.4).
  
  
  
  Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism.
authors: From the *Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; †Department of Otolaryngology/ Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland; ‡Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; §Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; ‖Department of Pharmacy, and Department of Pediatrics, Johns Hopkins Hospital, Baltimore, Maryland ¶Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; and #Department of Anesthesiology, University of Colorado, Aurora, Colorado.
authors: Nicholas M
authors: NM
authors: Dalesio
authors: Craig W
authors: CW
authors: Hendrix
authors: Douglas Hale
authors: DH
authors: McMichael
authors: Carol B
authors: CB
authors: Thompson
authors: Carlton K K
authors: CK
authors: Lee
authors: Huy
authors: H
authors: Pho
authors: Rafael S
authors: RS
authors: Arias
authors: Rachael Rzasa
authors: RR
authors: Lynn
authors: Jeffrey
authors: J
authors: Galinkin
authors: Myron
authors: M
authors: Yaster
authors: Robert H
authors: RH
authors: Brown
authors: Alan R
authors: AR
authors: Schwartz
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006207:Half-Life; D020738:Leptin / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008657:Metabolic Clearance Rate; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009022:Morphine Derivatives; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype
chemical_list: D000701:Analgesics, Opioid; D020738:Leptin; D009022:Morphine Derivatives; D009020:Morphine; C018108:morphine-3-glucuronide