The pharmacokinetics of co-administered lisinopril and hydrochlorothiazide

Co-administration of drugs with complementary action is a rational approach to the treatment of hypertension provided that the drugs are free of mutual pharmacokinetic interactions. The pharmacokinetics of single doses of lisinopril 10 mg alone, hydrochlorothiazide 12.5 mg alone, both drugs given concomitantly, and both given in a fixed combination tablet were studied in 24 healthy volunteers (including four women) using a randomized four-way crossover design with each treatment separated by 2 weeks. Timed blood and urine samples were collected for measurement of peak serum levels, area under the concentration vs time curve (AUC) and urinary recovery of lisinopril and hydrochlorothiazide. When given alone, peak serum levels of lisinopril (attained 6-8 hours post dose) were 44 ng/ml. Urinary recovery was 17.6% of the dose. Mean values after treatment with the combination tablet were only 2-6% lower, and co-administration with hydrochlorothiazide in free combination gave mean values 7% higher than the fixed-dose combination. Time to peak serum levels did not vary between treatments. Dosing with hydrochlorothiazide alone resulted in a mean peak serum concentration of 53 ng/ml, 2-6 hours post dose. The combination tablet resulted in a peak serum level and AUC for hydrochlorothiazide about 10% lower. The corresponding values for the free combination were only about 7% lower. The results indicate no clinically relevant pharmacokinetic interaction between the two components when administered in a single tablet.