Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse
Piperonyl butoxide (PBO) is a popular insecticide synergist present in thousands of commercial, agricultural, and household products. PBO inhibits cytochrome P450 activity, impairing the ability of insects to detoxify insecticides. PBO was recently discovered to also inhibit Sonic hedgehog signaling...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Toxicology Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214750023001099 |
| _version_ | 1797386805069217792 |
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| author | Alyssa E. Jenkins Cameron O. Scarlett Tyler G. Beames Kenneth S. Rivera-González Alexander A. Martin Miranda R. Sun Paul R. Hutson Robert J. Lipinski |
| author_facet | Alyssa E. Jenkins Cameron O. Scarlett Tyler G. Beames Kenneth S. Rivera-González Alexander A. Martin Miranda R. Sun Paul R. Hutson Robert J. Lipinski |
| author_sort | Alyssa E. Jenkins |
| collection | DOAJ |
| description | Piperonyl butoxide (PBO) is a popular insecticide synergist present in thousands of commercial, agricultural, and household products. PBO inhibits cytochrome P450 activity, impairing the ability of insects to detoxify insecticides. PBO was recently discovered to also inhibit Sonic hedgehog signaling, a pathway required for embryonic development, and rodent studies have demonstrated the potential for in utero PBO exposure to cause structural malformations of the brain, face, and limbs, or more subtle neurodevelopmental abnormalities. The current understanding of the pharmacokinetics of PBO in mice is limited, particularly with respect to dosing paradigms associated with developmental toxicity. To establish a pharmacokinetic (PK) model for oral exposure, PBO was administered to female C57BL/6J mice acutely by oral gavage (22–1800 mg/kg) or via diet (0.09 % PBO in chow). Serum and adipose samples were collected, and PBO concentrations were determined by HPLC-MS/MS. The serum concentrations of PBO were best fit by a linear one-compartment model. PBO concentrations in visceral adipose tissue greatly exceeded those in serum. PBO concentrations in both serum and adipose tissue decreased quickly after cessation of dietary exposure. The elimination half-life of PBO in the mouse after gavage dosing was 6.5 h (90 % CI 4.7–9.5 h), and systemic oral clearance was 83.3 ± 20.5 mL/h. The bioavailability of PBO in chow was 41 % that of PBO delivered in olive oil by gavage. Establishment of this PK model provides a foundation for relating PBO concentrations that cause developmental toxicity in the rodent models to Sonic hedgehog signaling pathway inhibition. |
| first_indexed | 2024-03-08T22:14:40Z |
| format | Article |
| id | doaj.art-d969be1796154876ab493f0125a82c11 |
| institution | Directory Open Access Journal |
| issn | 2214-7500 |
| language | English |
| last_indexed | 2024-03-08T22:14:40Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Toxicology Reports |
| spelling | doaj.art-d969be1796154876ab493f0125a82c112023-12-19T04:17:00ZengElsevierToxicology Reports2214-75002023-12-0111310317Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouseAlyssa E. Jenkins0Cameron O. Scarlett1Tyler G. Beames2Kenneth S. Rivera-González3Alexander A. Martin4Miranda R. Sun5Paul R. Hutson6Robert J. Lipinski7Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USASchool of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USADepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USADepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USADepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USADepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USASchool of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Correspondence to: 1038 Rennebohm Hall, 777 Highland Ave, Madison, WI 53705, USA.Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA; Correspondence to: 2015 Linden Dr., Madison, WI 53706, USA.Piperonyl butoxide (PBO) is a popular insecticide synergist present in thousands of commercial, agricultural, and household products. PBO inhibits cytochrome P450 activity, impairing the ability of insects to detoxify insecticides. PBO was recently discovered to also inhibit Sonic hedgehog signaling, a pathway required for embryonic development, and rodent studies have demonstrated the potential for in utero PBO exposure to cause structural malformations of the brain, face, and limbs, or more subtle neurodevelopmental abnormalities. The current understanding of the pharmacokinetics of PBO in mice is limited, particularly with respect to dosing paradigms associated with developmental toxicity. To establish a pharmacokinetic (PK) model for oral exposure, PBO was administered to female C57BL/6J mice acutely by oral gavage (22–1800 mg/kg) or via diet (0.09 % PBO in chow). Serum and adipose samples were collected, and PBO concentrations were determined by HPLC-MS/MS. The serum concentrations of PBO were best fit by a linear one-compartment model. PBO concentrations in visceral adipose tissue greatly exceeded those in serum. PBO concentrations in both serum and adipose tissue decreased quickly after cessation of dietary exposure. The elimination half-life of PBO in the mouse after gavage dosing was 6.5 h (90 % CI 4.7–9.5 h), and systemic oral clearance was 83.3 ± 20.5 mL/h. The bioavailability of PBO in chow was 41 % that of PBO delivered in olive oil by gavage. Establishment of this PK model provides a foundation for relating PBO concentrations that cause developmental toxicity in the rodent models to Sonic hedgehog signaling pathway inhibition.http://www.sciencedirect.com/science/article/pii/S2214750023001099Piperonyl butoxidePharmacokineticsMouse |
| spellingShingle | Alyssa E. Jenkins Cameron O. Scarlett Tyler G. Beames Kenneth S. Rivera-González Alexander A. Martin Miranda R. Sun Paul R. Hutson Robert J. Lipinski Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse Toxicology Reports Piperonyl butoxide Pharmacokinetics Mouse |
| title | Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse |
| title_full | Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse |
| title_fullStr | Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse |
| title_full_unstemmed | Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse |
| title_short | Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse |
| title_sort | pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse |
| topic | Piperonyl butoxide Pharmacokinetics Mouse |
| url | http://www.sciencedirect.com/science/article/pii/S2214750023001099 |
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