EFFECT OF ACUTE AND CHRONIC MODERATE HYPOXIA ON DILTIAZEM KINETICS AND METABOLISM IN THE DOG

The aim of this study was to assess whether moderate hypoxia affects t he disposition of diltiazem. Six male beagle dogs received diltiazem ( 0.6 mg/kg) on three occasions: (1) while breathing air, i.e. during no rmoxia; (2) 1 h after initiating exposure to a FiO2 Of 0.08, a FiCO2 o f 0.035 and a FiN2 of 0.885, i.e. during acute hypoxia and normocapnia , and (3) during chronic hypoxia, i.e. after 120 h of exposure to a Fi O2 Of 0.08. Multiple blood samples were withdrawn and urine was collec ted to assay diltiazem and metabolites [N-desmethyl diltiazem (MA), de acetyl diltiazem (DAD) and N-desmethyl deacetyl diltiazem (M2)]. Breat hing air, mean arterial partial pressure of oxygen was 83.2 +/- 3.2; d uring acute hypoxia 42.2 +/- 0.7; and during chronic hypoxia, 41.9 +/- 0.6 mm Hg. Acute hypoxia did not alter diltiazem disposition. Compare d to dogs with normoxia, chronic hypoxia reduced diltiazem metabolic c learance, from 64 +/- 3 to 51 +/- 5 ml/min/kg (p < 0.05), as well as i ts volume of distribution, from 11.4 +/- 1.2 to 9.1 +/- 0.3 liters/kg (p < 0.05). Chronic hypoxia decreased the fraction of diltiazem metabo lic clearance, normalized by the glomerular filtration rate, generatin g the M2 metabolite, although this experimental condition did not affe ct the formation of MA or DAD. It is concluded that chronic moderate h ypoxia reduced diltiazem systemic 'clearance because it decreased sele cted pathways of biotransformation.