The hypomagnesaemic action of FK506: urinary excretion of magnesium and calcium and the role of parathyroid hormone

A side-effect of the immunosuppressive drug FK506 (Prograf; tacrolimus) is hypomagnesaemia. We have investigated the effects: of short-term (7-day) tr eatment of rats with FK506, using a protocol designed to indicate whether t here are modifications in the renal tubular handling of magnesium and other electrolytes, or in the tissue deposition of magnesium, which may account for the hypomagnesaemia. We have also investigated whether parathyroid horm one has a role in the observed hypomagnesaemia. Two studies have been perfo rmed; in the first we administered FK506 (0.5 mg.kg(-1) body weight.day(-1) ) or vehicle by intraperitoneal injection for 7 days, and then housed the r ats in metabolic cages for the 24 h collection of urine. At the end of the metabolic cage period, the animals were anaesthetized, and blood and tissue samples were taken for analysis. In the second set of experiments the dosa ge regime was identical, but at the end of the treatment period the animals were anaesthetized for implantation of arterial and venous cannulae, and t hen received a saline (plus inulin) infusion for 6 h, during which time blo od and urine samples were collected. The dose of FK506 employed did not dec rease the glomerular filtration rate. FK506 elicited hypomagnesaemia in bot h sets of experiments, accompanied by inappropriately high fractional excre tion of magnesium. There was also evidence of disruption of the normal rena l reabsorption of calcium, but this did not result in hypocalcaemia. Plasma parathyroid hormone activity was not significantly different between the t wo groups, and there was no evidence of altered tissue content of magnesium in kidney, liver, heart, skeletal muscle or bone. The study confirms that hypomagnesaemia is a significant side-effect of FK506, even at a relatively low dose which did not decrease the glomerular filtration rate. The effect is not due to a decrease in parathyroid hormone release, or to translocati on of magnesium from plasma to tissues, but does reflect decreased renal tu bular magnesium (and calcium) reabsorption.