Session Type: ePosters
Session Title: ePosters
Authors(s): I. Slarve, M. Slarve, J. Olson, J. Adler-Moore
Authors Affiliations(s): California State Polytechnic University, Pomona, United States
Third Party Affiliation: N/A
Background:
Type 2 diabetes mellitus (T2DM), which occurs often in obese individuals, can negatively impact immune function along with compromised blood circulation, increasing susceptibility to fungal infections. In this study, a murine obesity model was used to investigate the effects of T2DM on serum and tissue pharmacokinetics of the antifungal drug, liposomal amphotericin B (L-AmB).
Methods:Male uninfected ICR mice (n=40) were fed a high fat (60%) diet to induce obesity (40-45g). Control mice (n=40) were fed a standard fat (10%) diet to maintain normal weights (32-35g). Obese mice were induced to become T2DM with a fasting blood glucose level of >200mg/dL by intraperitoneal injections with nicotinamide (60mg/kg) and streptozotocin (100mg/kg). All mice received intravenous L-AmB (5mg/kg/day) for 7 days. Blood and tissues were collected at 0.5h, 1h, 2h, 6h, 12h, 24h, 48h, and 72h following the last drug treatment (n=5 mice/timepoint). Drug concentrations in the samples were determined by a standardized bioassay. Area under the curve (AUC0-last) was used as a comparative measure of L-AmB tissue and serum drug exposure.
Results:Based on AUC0-last, uninfected T2DM mice had significantly more L-AmB than control non-T2DM mice in the liver (14776 vs. 8205 ug*h/g, p=0.008), lungs (1035 vs. 754 ug*h/g, p=0.008), and spleen (22861 vs. 16660 ug*h/g, p=0.03). In comparison, T2DM mice had significantly less drug than control mice in the serum (235 vs. 376 ug*h/mL, p=0.03), kidneys (617 vs. 1363 ug*h/g, p=0.008), and adipose tissue (40 vs. 67 ug*h/g, p=0.03).
Conclusions:Compared to non-T2DM control, uninfected mice, weight-based dosing of T2DM mice resulted in significantly higher liver, lung, and spleen L-AmB levels, while drug levels in serum, kidneys, and adipose tissue were significantly lower. This murine study suggests that L-AmB dosing in T2DM mice may result in liver toxicity given the observed high drug liver levels, but if the levels are too low in other tissues, like the kidneys, this may result in decreased efficacy.
Keyword(s): liposomal amphotericin B, pharmacokinetics, diabetesCOI Fees: Yes COI Institutional Grants: Yes COI Stock Options: Yes
Session Type: ePosters
Session Title: ePosters
Authors(s): I. Slarve, M. Slarve, J. Olson, J. Adler-Moore
Authors Affiliations(s): California State Polytechnic University, Pomona, United States
Third Party Affiliation: N/A
Background:
Type 2 diabetes mellitus (T2DM), which occurs often in obese individuals, can negatively impact immune function along with compromised blood circulation, increasing susceptibility to fungal infections. In this study, a murine obesity model was used to investigate the effects of T2DM on serum and tissue pharmacokinetics of the antifungal drug, liposomal amphotericin B (L-AmB).
Methods:Male uninfected ICR mice (n=40) were fed a high fat (60%) diet to induce obesity (40-45g). Control mice (n=40) were fed a standard fat (10%) diet to maintain normal weights (32-35g). Obese mice were induced to become T2DM with a fasting blood glucose level of >200mg/dL by intraperitoneal injections with nicotinamide (60mg/kg) and streptozotocin (100mg/kg). All mice received intravenous L-AmB (5mg/kg/day) for 7 days. Blood and tissues were collected at 0.5h, 1h, 2h, 6h, 12h, 24h, 48h, and 72h following the last drug treatment (n=5 mice/timepoint). Drug concentrations in the samples were determined by a standardized bioassay. Area under the curve (AUC0-last) was used as a comparative measure of L-AmB tissue and serum drug exposure.
Results:Based on AUC0-last, uninfected T2DM mice had significantly more L-AmB than control non-T2DM mice in the liver (14776 vs. 8205 ug*h/g, p=0.008), lungs (1035 vs. 754 ug*h/g, p=0.008), and spleen (22861 vs. 16660 ug*h/g, p=0.03). In comparison, T2DM mice had significantly less drug than control mice in the serum (235 vs. 376 ug*h/mL, p=0.03), kidneys (617 vs. 1363 ug*h/g, p=0.008), and adipose tissue (40 vs. 67 ug*h/g, p=0.03).
Conclusions:Compared to non-T2DM control, uninfected mice, weight-based dosing of T2DM mice resulted in significantly higher liver, lung, and spleen L-AmB levels, while drug levels in serum, kidneys, and adipose tissue were significantly lower. This murine study suggests that L-AmB dosing in T2DM mice may result in liver toxicity given the observed high drug liver levels, but if the levels are too low in other tissues, like the kidneys, this may result in decreased efficacy.
Keyword(s): liposomal amphotericin B, pharmacokinetics, diabetesCOI Fees: Yes COI Institutional Grants: Yes COI Stock Options: Yes
Session Type: ePosters
Session Title: ePosters
Authors(s): I. Slarve, M. Slarve, J. Olson, J. Adler-Moore
Authors Affiliations(s): California State Polytechnic University, Pomona, United States
Third Party Affiliation: N/A
Background:
Type 2 diabetes mellitus (T2DM), which occurs often in obese individuals, can negatively impact immune function along with compromised blood circulation, increasing susceptibility to fungal infections. In this study, a murine obesity model was used to investigate the effects of T2DM on serum and tissue pharmacokinetics of the antifungal drug, liposomal amphotericin B (L-AmB).
Methods:Male uninfected ICR mice (n=40) were fed a high fat (60%) diet to induce obesity (40-45g). Control mice (n=40) were fed a standard fat (10%) diet to maintain normal weights (32-35g). Obese mice were induced to become T2DM with a fasting blood glucose level of >200mg/dL by intraperitoneal injections with nicotinamide (60mg/kg) and streptozotocin (100mg/kg). All mice received intravenous L-AmB (5mg/kg/day) for 7 days. Blood and tissues were collected at 0.5h, 1h, 2h, 6h, 12h, 24h, 48h, and 72h following the last drug treatment (n=5 mice/timepoint). Drug concentrations in the samples were determined by a standardized bioassay. Area under the curve (AUC0-last) was used as a comparative measure of L-AmB tissue and serum drug exposure.
Results:Based on AUC0-last, uninfected T2DM mice had significantly more L-AmB than control non-T2DM mice in the liver (14776 vs. 8205 ug*h/g, p=0.008), lungs (1035 vs. 754 ug*h/g, p=0.008), and spleen (22861 vs. 16660 ug*h/g, p=0.03). In comparison, T2DM mice had significantly less drug than control mice in the serum (235 vs. 376 ug*h/mL, p=0.03), kidneys (617 vs. 1363 ug*h/g, p=0.008), and adipose tissue (40 vs. 67 ug*h/g, p=0.03).
Conclusions:Compared to non-T2DM control, uninfected mice, weight-based dosing of T2DM mice resulted in significantly higher liver, lung, and spleen L-AmB levels, while drug levels in serum, kidneys, and adipose tissue were significantly lower. This murine study suggests that L-AmB dosing in T2DM mice may result in liver toxicity given the observed high drug liver levels, but if the levels are too low in other tissues, like the kidneys, this may result in decreased efficacy.
Keyword(s): liposomal amphotericin B, pharmacokinetics, diabetesCOI Fees: Yes COI Institutional Grants: Yes COI Stock Options: Yes
Session Type: ePosters
Session Title: ePosters
Authors(s): I. Slarve, M. Slarve, J. Olson, J. Adler-Moore
Authors Affiliations(s): California State Polytechnic University, Pomona, United States
Third Party Affiliation: N/A
Background:
Type 2 diabetes mellitus (T2DM), which occurs often in obese individuals, can negatively impact immune function along with compromised blood circulation, increasing susceptibility to fungal infections. In this study, a murine obesity model was used to investigate the effects of T2DM on serum and tissue pharmacokinetics of the antifungal drug, liposomal amphotericin B (L-AmB).
Methods:Male uninfected ICR mice (n=40) were fed a high fat (60%) diet to induce obesity (40-45g). Control mice (n=40) were fed a standard fat (10%) diet to maintain normal weights (32-35g). Obese mice were induced to become T2DM with a fasting blood glucose level of >200mg/dL by intraperitoneal injections with nicotinamide (60mg/kg) and streptozotocin (100mg/kg). All mice received intravenous L-AmB (5mg/kg/day) for 7 days. Blood and tissues were collected at 0.5h, 1h, 2h, 6h, 12h, 24h, 48h, and 72h following the last drug treatment (n=5 mice/timepoint). Drug concentrations in the samples were determined by a standardized bioassay. Area under the curve (AUC0-last) was used as a comparative measure of L-AmB tissue and serum drug exposure.
Results:Based on AUC0-last, uninfected T2DM mice had significantly more L-AmB than control non-T2DM mice in the liver (14776 vs. 8205 ug*h/g, p=0.008), lungs (1035 vs. 754 ug*h/g, p=0.008), and spleen (22861 vs. 16660 ug*h/g, p=0.03). In comparison, T2DM mice had significantly less drug than control mice in the serum (235 vs. 376 ug*h/mL, p=0.03), kidneys (617 vs. 1363 ug*h/g, p=0.008), and adipose tissue (40 vs. 67 ug*h/g, p=0.03).
Conclusions:Compared to non-T2DM control, uninfected mice, weight-based dosing of T2DM mice resulted in significantly higher liver, lung, and spleen L-AmB levels, while drug levels in serum, kidneys, and adipose tissue were significantly lower. This murine study suggests that L-AmB dosing in T2DM mice may result in liver toxicity given the observed high drug liver levels, but if the levels are too low in other tissues, like the kidneys, this may result in decreased efficacy.
Keyword(s): liposomal amphotericin B, pharmacokinetics, diabetesCOI Fees: Yes COI Institutional Grants: Yes COI Stock Options: Yes