Pharmacokinetics of diltiazem and propranolol when administered alone and in combination

Multiple oral doses of diltiazem (DTZ) and propranolol (PPL, 60 mg every 8 h daily for 13 doses) were administered to 14 healthy volunteers alone and in combination on three separate occasions. Serial blood samples were collected up to 24 h after dose 13 on day 5 to determine possible pharmacokinetic interactions between the two drugs. When administered alone, DTZ concentration peaked at 161.4 ng ml-1 3 h following the final dose with an elimination half-life of 6.1 h. DTZ oral clearance was 65.1 l h-1. PPL did not affect DTZ oral clearance and half-life during the combination treatment. However, DTZ tmax was extended from 2.9 h to 3.5 h (p less than 0.05) and Cmax was 144.7 ng ml-1. Unlike the parent drug DTZ, desacetyldiltiazem (DAD) plasma profile was elevated during the combination treatment. DAD Cmax and AUC both increased approximately 20 per cent (p less than 0.05). PPL pharmacokinetics were altered as well. Oral clearance of PPL decreased from 80.4 l h-1 to 61.0 l h-1 while the half-life increased from 5.9 h to 8.0 h (p less than 0.05). PPL Cmax increased from 155.1 ng ml-1 to 167.5 ng ml-1.