Hruska, Matthew Walter
(2005)
CHARACTERIZATION OF CYTOCHROME P450 2C8 ACTIVITY IN VIVO: PHARMACOGENETIC AND PHARMACOKINETIC STUDIES OF ROSIGLITAZONE METABOLISM.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The Cytochrome P450 (CYP) superfamily of drug metabolizing enzymes is responsible for the metabolism of a variety of drugs and endogenous compounds. The CYP2C enzyme subfamily (CYP2C8, CYP2C9, and CYP2C19) mediates the metabolism of approximately twenty percent of these compounds. While CYP2C9 and CYP2C19 have been well characterized in vivo, relatively little is known about the in vivo contribution of CYP2C8. However, as the number of substrates and interest in polymorphic expression has grown, so too has the importance of CYP2C8. The in vivo relevance of CYP2C8 can be estimated with a drug predominately metabolized by this enzyme as a probe substrate. Thus, the overall purpose of this research was to investigate the utility of rosiglitazone as an in vivo probe of CYP2C8 activity. To accomplish this goal, we characterized the pharmacokinetics of rosiglitazone in the presence of the CYP2C8 inhibitor, trimethoprim, the CYP inducer, St. John's wort, and in subjects genotyped for variant CYP2C8 alleles. Novel liquid chromatographic methods were developed for the determination of rosiglitazone and trimethoprim plasma concentrations with fluorescence and ultraviolet wavelength detection, respectively. CYP2C8 genotyping was accomplished with a newly developed method based on Pyrosequencing technology, which facilitates high-throughput analysis in a cost-effective manner. Trimethoprim was an effective inhibitor of rosiglitazone metabolism in vitro and it increased rosiglitazone concentrations in vivo by 31%. In addition, there was a strong relationship (r2=0.97, p=0.0021) between trimethoprim plasma concentration and fold inhibition in subjects who did not carry the CYP2C8*3 allele, suggesting genotype influences the extent of CYP2C8 inhibition. Administration of St. John's wort increased rosiglitazone clearance by 35%, but CYP2C8 genotype did not affect the magnitude of induction. Finally, genotype did not affect basal rosiglitazone metabolism. Since changes have been observed with other CYP2C8 metabolized drugs, polymorphic effects of CYP2C8 may be substrate dependent. In conclusion, these results support the use of rosiglitazone as an in vivo probe of CYP2C8 activity, as it is affected by CYP2C8 inhibitors and inducers. The clinical benefits of CYP2C8 substrates may be influenced by these and other CYP2C8 modulators and therefore rosiglitazone could serve as a probe to detect these interactions.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
31 January 2005 |
| Date Type: |
Completion |
| Defense Date: |
4 October 2004 |
| Approval Date: |
31 January 2005 |
| Submission Date: |
22 December 2004 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
drug metabolism |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-12222004-121224/, etd-12222004-121224 |
| Date Deposited: |
10 Nov 2011 20:11 |
| Last Modified: |
15 Nov 2016 13:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10447 |
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