PT  - JOURNAL ARTICLE
AU  - Tomohiro Nishimura
AU  - Yoshiaki Seki
AU  - Kazuko Sato
AU  - Takuya Chishu
AU  - Noriko Kose
AU  - Tetsuya Terasaki
AU  - Young-Sook Kang
AU  - Yoshimichi Sai
AU  - Emi Nakashima
TI  - Enhancement of Zidovudine Uptake by Dehydroepiandrosterone Sulfate in Rat Syncytiotrophoblast Cell Line TR-TBT 18d-1
AID  - 10.1124/dmd.108.021345
DP  - 2008 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 2080--2085
VI  - 36
IP  - 10
4099  - http://dmd.aspetjournals.org/content/36/10/2080.short
4100  - http://dmd.aspetjournals.org/content/36/10/2080.full
SO  - Drug Metab Dispos2008 Oct 01; 36
AB  - AZT (3′-azido-3′-deoxythymidine; zidovudine), which is used for the prevention of mother-to-child transmission of HIV-1, is transplacentally transferred to the fetus across the blood-placenta barrier, which is composed of syncytiotrophoblasts. We recently showed that apical uptake of AZT by syncytiotrophoblasts is mediated by saturable transport system(s) in the TR-TBT 18d-1 cell line, and the cellular accumulation of AZT was increased in the presence of dehydroepiandrosterone sulfate (DHEAS). Here, we aimed to clarify the mechanism of this effect of DHEAS. Inhibitors of efflux transporters, including breast cancer resistance protein, P-glycoprotein, and multidrug resistance proteins, had little effect on the cellular accumulation of AZT in TR-TBT 18d-1. Kinetic study revealed that the rate constant for AZT uptake was greatly increased in the presence of 1 mM DHEAS. These results suggested that the effect of DHEAS was because of enhancement of the uptake process(es), rather than inhibition of efflux. When AZT uptake was analyzed according to the Michaelis-Menten equation, the estimated Michaelis constant, Km, for AZT uptake in the presence of 1 mM DHEAS was lower than that in its absence, whereas maximum uptake velocity, Vmax, and nonsaturable uptake clearance, kns, were similar in the presence and absence of DHEAS, indicating that DHEAS may change the recognition characteristics of the transporter for AZT in TR-TBT 18d-1. Thus, the increase of AZT uptake in TR-TBT 18d-1 cells in the presence of DHEAS was concluded to be because of a DHEAS-induced change in the affinity of AZT uptake system, although the transporter responsible for AZT uptake has not been identified. The American Society for Pharmacology and Experimental Therapeutics