193 IN VIVD AND IN VITRO INHIBITION CF HEPATIC OXIDATIVE DRUG MEZ%B(K~SM BY ~ .

P. Mosca, P. Bcnazzi, F. Orlandi. University of Ancona School of Medicine and General Hospi tai, Ancona, Italy.

~etnconazole(Kc), a broad spectrlam antifungal drug, has been recently recognized as a cau

se of hepatic injury. The mechanis~ of the adverse reaction rema/ns unclear: a metabolic idio

sincrasy has been suggested (Gastroenterology,1984,86:503). However as substituted imidazole

Kc might be expected to interfere with the hepatic microsomal mixed function oxidases. Aim of

the present study was to evaluate the effect of Kc on some pathways of the hepatic drug bio

transformation systems both in vitro and in vivo. Ethylnorphine demethylase (E-DM) and aniline

hydroxylase (A-OH) activities were determined on rat liver microscmes in the presence of incre

asing amounts of Kc. Both wmre inhibited in an exponential fashion. The E-DM inhibition appe_

ared at a concentration of Kc>0.5 ~mol and was almost complete at concentrations>250 ~mol.The

inhibition was of the mixed type. A comparable but w~aker effect was observed for A-OH. A si

gnificant inhibition of E-~M activity was also observed when Kc was administered to rats in vi~o (I00 mg/kg) either orally for 7 days (average 40% reduction, P<0.02) or intraperitoneal ly for 4 days (average 50% reduction, P<0.05). Neither the amount of cyt P-450, nor NADPH cyt

c reductase or A-OH activities were affected at the doses considered. These data are in agre

ement with previous report (Hepatology,1983,3:360 Abstr) showing an interference of Kc with

hepatic oxidative drug metabolima and suggest that this mechanism might be implied in the un_

wanted side effects of th~.rapy with Kc.

194 EFFECT OF ACUTE ACID-BASE DISTURBANCES ON BILIARY HCO3 SECRETION IN THE RAT.

C. Munoz, M. Corbic, M. Dumont, G. de Cou~t, S. Erlinger. INSERM U-24, H~pital Beaujon, Clichy, France

Biliary HCO~ secretion by the hepatocyte may play a role in bile formation;its mechanism is unknown. Ursodeoxycholic acid (UDCA) increases both bile flow and biliary HCO~ concentration in the rat. The aim of this study was to determine the effect of pH, PCO 2 and HCO~ concentra- tion of blood on bile flgw and biliary HC0~ secretion in the bile fistula rat.

Experiments were performed during UDCA infusion (I Hmol.min=l.100g -I) in control conditions and during acute acid-base disturbances. Metabolic acidosis or alkalosis were induced by HCI or NaHCO 3 infusions, and respiratory acidosis and alkalosis were created respectively by adding CO2 to the inspired gas or by hyperventilation in artificially ventilated animals.

During UDCA infusion, HCO~ concentration was always higher in bile than in plasma. During metabolic disturbances, changing the plasma HCO~ concentration from 9.8 to 30.2 mM signifi- cantly stimulated biliary HCO~ output by I13%. During respiratory disturbances, changing the plasma PCO2 from 25.5 to 59.8 mmHg also significantly increased biliary HC03 output by 90%. Biliary HCO~ secretion was thus independent of plasma pH. When all rats were considered toge- ther, bile flow was positively correlated with biliary HCO~ concentration and secretion (P<0.001) and negatively correlated with biliary chloride concentration (P<0.OI). Acetazola- mide significantly inhibited UDCA-induced choleresis and biliary HCO~ output by 20 and 22%.

These results show that during UDCA infusion in the ra~, there is a direct relationship between bile flow and HCO~ output. They suggest that biliary HCO~ secretion is an active process, strongly affected by plasma HCO~ concentration and PCO2, and not by plasma pH, and involves carbonic anhydrase.

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