Physiological disposition of guanethidine in the rat and its uptake by heart slices

Abstract

Guanethidine, administered intravenously to rats (3·5–28 mg/kg) becomes localized in a number of tissues. After 2 hr, the tissue/plasma concentration ratios are about 20 for heart, 10–12 for lung and intestine, 5–6 for skeletal muscle, spleen and kidney, and 2 for liver. The general pattern of distribution changes with time: localization is greatest in liver and kidney in the beginning, and later becomes greatest in heart and skeletal muscle. Although guanethidine is rapidly metabolized and excreted in urine during the first hr after administration, it is well protected once it has become localized in heart and skeletal muscle. After the first hr, the biological half-time of the drug is approximately 8 hr. Ultra-filtration studies show that guanethidine is bound to tissue components of heart, skeletal muscle, kidney and liver, with heart components having the greatest affinity for the compound. The drug is not appreciably bound to plasma proteins. Slices of rat heart take up guanethidine by two different processes, one of which requires oxygen, is saturable, and is blocked by amphetamine. The uptake and accumulation of guanethidine by the heart is discussed in terms of diffusion, specialized transport processes, and intracellular binding, and the possibility is considered that symphathetic nerve endings constitute one of the sites of accumulation.