The effects of an orally active inhibitor (UK 79300) of the neutral metalloendopeptidase EC 3.4.24.11 were investigated in six healthy male volunteers maintained on a constant diet (150 mmol sodium/day and 80 mmol potassium/day). Subjects were studied in a random order, single-blind study on two occasions, each 48 hours in length, when they were given UK 79300 (25 or 50 mg p.o.) or placebo at 12-hour intervals (each agent for 24 hours). The endopeptidase inhibitor enhanced plasma concentrations of atrial natriuretic factor in association with suppression of both plasma renin activity and aldosterone concentrations. Twenty-four-hour urinary excretion of sodium was doubled by UK 79300, and the urinary excretion rates of phosphorus, atrial natriuretic factor immunoreactivity, and cyclic guanosine monophosphate were also significantly enhanced, whereas urinary aldosterone excretion was halved. The profile of biological effects closely paralleled those previously reported with low dose infusions of atrial natriuretic factor in humans and animals. Therapeutic trials of such inhibitors are now indicated for hypertension or heart failure together with further studies to clarify the underlying mechanisms of action. {Hypertension 1990;16:269-276) A trial natriuretic factor (ANF) exhibits a broad / \ range of actions, all of which may be perti-/ % nent in volume-pressure homeostasis. In addition to natriuretic and diuretic activity, ANF inhibits the renin-angiotensin-aldosterone system (RAAS), contracts plasma volume by extrarenal mechanisms, and is a vasodilator. This spectrum of activity suggests ANF may have therapeutic potential in conditions such as hypertension and heart failure. Recent studies incorporating administration of very low or "physiological" doses of exogenous ANF to both normal volunteers and patients with hypertension demonstrate the capacity of very small shifts in plasma concentrations of ANF to inhibit the RAAS, induce natriuresis, and with sustained administration, exert a salutary hypotensive effect in patients with essential hypertension. bond producing an open-ring structure, which our group has identified as being present in significant quantities in human plasma. 5Parenteral administration of the endopeptidase inhibitor (UK 69578) in animal studies and in humans has resulted in enhanced plasma ANF concentrations with an associated increase in natriuresis and potentiation of biological responses to exogenous ANF.6 -8 We have investigated the effects of two doses of an oral prodrug, UK 79300 (which is hydrolyzed to release the active endopeptidase inhibitor UK 73967), on renal and hormonal indexes and blood pressure in a group of healthy volunteers. MethodsWe studied six healthy male volunteers from 18 to 33 years of age (mean 21 years) who weighed 66-75 kg (mean 70.9 kg); none were taking medication. All subjects gave written, informed consent before par-

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1. Following intravenous administration to animals at 2.5 mg/kg, darifenacin exhibited terminal plasma half-lifes < 2 h due to high plasma clearance (with respect to blood flow) and volumes of distribution greater than total body water. 2. Following oral administration to animals at doses > 4 mg/kg there was evidence of saturation of clearance since oral AUCs exceeded those expected from the high plasma clearances. In addition, terminal plasma half-lifes were greater than those estimated from intravenous administration. 3. In man, oral clearance was high with respect to liver blood flow. 4. Following oral administration of the radiolabelled drug to animals and man, unchanged darifenacin was only a minor component of the faecal radioactivity indicating that darifenacin was well absorbed from the gut. 5. Darifenacin was metabolized by three main routes in all species: monohydroxylation, oxidative dihydrobenzfuran ring opening and N-dealkylation. There were no marked species differences in the metabolism of darifenacin.

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1. Candoxatrilat, an active neutral endopeptidase inhibitor, was released rapidly from the inactive prodrug candoxatril in vivo in mouse, rat, rabbit, dog and man. 2. Oral doses of [14C]-candoxatril were cleared rapidly, mostly by ester hydrolysis to candoxatrilat, in mouse, dog and man. A complementary intravenous study in man with [14C]-candoxatrilat showed that the active drug was virtually completely renally cleared. Neither candoxatril nor candoxatrilat underwent chiral inversion in man. 3. Systemic availability of candoxatrilat from the oral prodrug was estimated to be 88, 53, 42, 17 and 32% in mouse, rat, rabbit, dog and man respectively. Plasma clearance of candoxatril was too rapid to enable pharmacokinetic parameter calculation in mouse and rabbit; for man, the apparent oral clearance was 57.9 ml/min/kg and the elimination half-life was 0.46 h. 4. For intravenous candoxatrilat, total plasma clearance values were 32, 15, 5.5, 5.8 and 1.9 ml/min/kg for mouse, rat, rabbit, dog and man respectively. Renal clearance values were 8.7, 7.2, 2.9 and 1.7 ml/min/kg for mouse, rat, dog and man and these approximate to the respective glomerular filtration rates. Allometric scaling with respect to bodyweight across the species allowed reasonable prediction of the above two clearance parameters in man.