Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model

Nicholas Dalesio, Craig Hendrix, Douglas Hale McMichael, Carol Thompson, Carlton K Lee, Huy Pho, Rafael S. Arias, Rachael Rzasa Lynn, Jeffrey Galinkin, Myron Yaster, Robert Howard Brown, Alan R Schwartz

Research output: Contribution to journalArticle

Abstract

BACKGROUND:: 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. METHODS:: 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. RESULTS:: 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). CONCLUSIONS:: 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.

Original languageEnglish (US)
JournalAnesthesia and Analgesia
DOIs
StateAccepted/In press - Oct 24 2016

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Leptin
Morphine
Pharmacokinetics
Obesity
Confidence Intervals
Diet
Obese Mice
Opioid Analgesics
Respiratory Center
Hunger
Respiratory Rate
Carbon Dioxide
Area Under Curve
Half-Life
Analysis of Variance

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model. / Dalesio, Nicholas; Hendrix, Craig; McMichael, Douglas Hale; Thompson, Carol; Lee, Carlton K; Pho, Huy; Arias, Rafael S.; Lynn, Rachael Rzasa; Galinkin, Jeffrey; Yaster, Myron; Brown, Robert Howard; Schwartz, Alan R.

In: Anesthesia and Analgesia, 24.10.2016.

Research output: Contribution to journalArticle

Dalesio, Nicholas ; Hendrix, Craig ; McMichael, Douglas Hale ; Thompson, Carol ; Lee, Carlton K ; Pho, Huy ; Arias, Rafael S. ; Lynn, Rachael Rzasa ; Galinkin, Jeffrey ; Yaster, Myron ; Brown, Robert Howard ; Schwartz, Alan R. / Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model. In: Anesthesia and Analgesia. 2016.
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title = "Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model",
abstract = "BACKGROUND:: 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. METHODS:: 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. RESULTS:: 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). CONCLUSIONS:: 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.",
author = "Nicholas Dalesio and Craig Hendrix and McMichael, {Douglas Hale} and Carol Thompson and Lee, {Carlton K} and Huy Pho and Arias, {Rafael S.} and Lynn, {Rachael Rzasa} and Jeffrey Galinkin and Myron Yaster and Brown, {Robert Howard} and Schwartz, {Alan R}",
year = "2016",
month = "10",
day = "24",
doi = "10.1213/ANE.0000000000001578",
language = "English (US)",
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TY - JOUR

T1 - Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model

AU - Dalesio, Nicholas

AU - Hendrix, Craig

AU - McMichael, Douglas Hale

AU - Thompson, Carol

AU - Lee, Carlton K

AU - Pho, Huy

AU - Arias, Rafael S.

AU - Lynn, Rachael Rzasa

AU - Galinkin, Jeffrey

AU - Yaster, Myron

AU - Brown, Robert Howard

AU - Schwartz, Alan R

PY - 2016/10/24

Y1 - 2016/10/24

N2 - BACKGROUND:: 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. METHODS:: 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. RESULTS:: 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). CONCLUSIONS:: 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.

AB - BACKGROUND:: 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. METHODS:: 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. RESULTS:: 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). CONCLUSIONS:: 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.

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