The fate of guanethidine in two hypertensive patients

Metabolites of [3H]‐guanethidine were identified in human urine. It was found that 90 per cent of the radioactivity in urine could be accounted for as guanethidine and two metabolites which had much less antihypertensive activity. After intramuscular injection, 50 per cent of the radioactive dose was eliminated in the urine in the first 2 to 3 days and 2 to 3% in the feces. Thereafter the dose left in the body declined exponentially with a half‐life of 9 to 10 days. Plasma level measurements indicated high renal clearance for guanethidine (300 ml. per minute). The hepatic clearance of the drug was also estimated to be high. The long half‐life of the drug is therefore not due to inefficient metabolism or renal clearance and must be due to a high degree of tissue localization. After an oral dose, plasma levels of the drug stayed approximately constant from 1 to 10 hours, indicating slow but continuous absorption of the drug, while radioactivity in the urine showed that absorption was incomplete. The ratio of metabolites to unchanged guanethidine in the urine was much larger after oral than after intramuscular administration of guanethidine to the same patient, suggesting that a significant amount of the drug was metabolized while passing through the liver. The results indicate that absorption, renal clearance, metabolism, and tissue uptake of guanethidine all play important parts in determining the amount of drug in the body of patients receiving regular treatment.