Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques.
BACKGROUND
Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT(1)) receptor (AT(1)R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using (11)C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques.


METHODS
Three male rhesus macaques were bolus intravenously administered [(11)C]telmisartan either alone or as a mixture with unlabeled telmisartan (1mg/kg). Dynamic PET images were acquired for 95min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain.


RESULTS
Telmisartan penetrated into the brain little but enough to block AT(1)R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT(1)R distribution was noted over the entire brain, even on tracer alone dosing.


CONCLUSIONS
Telmisartan penetrated into the brain enough to block AT(1)R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.
Bioimaging Research Laboratories, Astellas Pharma Inc., Tsukuba, Japan. akihiro.noda@astellas.com
Akihiro
A
Noda
Hiroshi
H
Fushiki
Yoshihiro
Y
Murakami
Hiroshi
H
Sasaki
Sosuke
S
Miyoshi
Hirotoshi
H
Kakuta
Shintaro
S
Nishimura
D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism* / Q000494:pharmacology; D001565:Benzoates / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003243:Consciousness; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D002250:Carbon Radioisotopes; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan