ABCB1 2677T and 3435T polymorphisms are associated with cilostazol-induced headache in phase I clinical trials

SK Cho1,2, K Park1,2. 1Yonsei University, Department of Pharmacology 120-752, Republic of Korea, 2Yonsei University, Brain Korea 21 Project for Medical Science, 120-752, Republic of Korea

Background

Cilostazol, a phosphodiesterase type 3 inhibitor, induces headache by increasing cyclic adenosine monophosphate levels and dilating arteries. Multidrug resistance protein 1 (MDR1, encoded by the ABCB1 gene) is expressed in vascular smooth muscle and involved in the transport of cilostazol. We investigated whether genetic variants of ABCB1 are associated with differential incidence of cilostazol-induced headache

Methods

The study had two components. First, we examined whether single nucleotide polymorphisms of the human ABCB1 gene are associated with the incidence of cilostazol-induced headache in 101 volunteers participating in six phase I cilostazol clinical trials. Second, using an in vitro functional analysis, we investigated whether cilostazol is a substrate of MDR1 and the genetic variants of MDR1 show different transport activity of cilostazol.

Results

ABCB1 c.2677G>T and c.3435C>T polymorphisms were associated strongly with the incidence of cilostazol-induced headache (G/A vs. T, P=0.006, OR=2.34; C vs. T, P=0.0003, OR=3.01; G/A2677T and C3435T, respectively). Logistic regression analysis with multiple clinical variables indicated that the presence of the T allele at the ABCB1 c.3435C>T locus is an independent determinant of headache incidence. Functional analysis indicated that cilostzol is a substrate of MDR1 and 893Ser-MDR1 (c.2677T) failed to transport cilostazol effectively.

Conclusion

ABCB1 c.2677G>T and c.3435C>T polymorphisms are related to the incidence of cilostazol-induced headache. Large-scale clinical trials are needed to confirm this finding.