Abstract
Acidic phospholipid binding plays an important role in determining the tissue distribution of basic drugs. This article describes the use of surface plasmon resonance to measure binding affinity (KD) of three basic drugs to phosphatidylserine, a major tissue acidic phospholipid. The data are incorporated into mechanistic tissue composition equations to allow prediction of the steady-state volume of distribution (Vss). The prediction accuracy of Vss using this approach is compared with the original methodology described by Rodgers et al. (J Pharm Sci 94:1259–1276), in which the binding to acidic phospholipids is calculated from the blood/plasma concentration ratio (BPR). The compounds used in this study [amlodipine, propranolol, and 3-dimethylaminomethyl-4-(4-methylsulfanyl-phenoxy)-benzenesulfonamide (UK-390957)] showed higher affinity binding to phosphatidylserine than to phosphatidylcholine. When the binding affinity to phosphatidylserine was incorporated into mechanistic tissue composition equations, the Vss was more accurately predicted for all three compounds by using the surface plasmon resonance measurement than by using the BPR to estimate acidic phospholipid binding affinity. The difference was particularly marked for UK-390957, a sulfonamide that has a high BPR due to binding to carbonic anhydrase. The novel approach described in this article allows the binding affinity of drugs to an acidic phospholipid (phosphatidylserine) to be measured directly and demonstrates the utility of the binding data in the prediction of Vss.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040253.
-
ABBREVIATIONS:
- BPR
- blood/plasma concentration ratio
- UK-390957
- 3-dimethylaminomethyl-4-(4-methylsulfanyl-phenoxy)-benzenesulfonamide
- DMSO
- dimethyl sulfoxide
- PBS
- phosphate-buffered saline
- SPR
- surface plasmon resonance
- AAFE
- absolute average fold error.
- Received April 26, 2011.
- Accepted July 14, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|