Backgrounds

Amlodipine is a second generation calcium channel blocker that has been widely used in the therapy of hypertension and angina pectoris. As a BCS class I drug with high aqueous solubility and high passive permeability, amlodipine has an unusually long Tmax of 4~9 hours after oral administration. Raušl et al. explained this long Tmax with enterohepatic circulation [1]. This hypothesis has been adopted in a recently published PBPK model [2].

However, the possibility of enterohepatic circulation of amlodipine is low.
➢ There is no evidence of amlodipine biliary excretion in human.
➢ While delayed Tmax (~ 4 h) of amlodipine was observed in rat after aqueous oral solution administration, studies in bile duct-cannulated rats (Ni et al. [3] and Walker et al. [4]) reported that no or less than 1% of the total dose was detected in the bile and that metabolism is the main clearance mechanism of amlodipine.

On the other hand, lysosomal trapping could be a more plausible explanation of the long Tmax of amlodipine. It has been proposed that lysosomal trapping could cause delayed absorption after oral administration of dextromethorphan [5] and pulmonary administration of Olodaterol [6]. Given that amlodipine has the identified common properties of lysosomotropic agents, such as a LogP > 2 (LogP = 3.0) and a basic pKa between 6.5 and 11 (basic pKa = 9.1), it could be sequestered in the lysosomes during the absorption and resulting in delayed Tmax. In addition, its lysosomal trapping potential has been confirmed by several in vitro cell based assays [7].

Thus, we proposed that the high lysosomal trapping in the enterocytes rather than enterohepatic circulation, is responsible for the long Tmax of amlodipine.

By Jin Dong, Viera Lukacova, Michael B Bolger, Grace Fraczkiewicz

ASCPT 2019 Annual Meeting, March 13-16, 2019, Washington, DC