The effect of right heart failure on theophylline clearance was investigated in rats in which right ventricular pressure overload was produced by pulmonary artery constriction (PAC). Fifteen wk after the surgery, compared to sham-operated controls (n = 9), PAC rats (n = 9) showed markedly elevated mean central venous pressure (11 +/- 3 vs 1.44 +/- 0.88 mm Hg, P = .0001), and increased right ventricular weight (0.229 +/- 0.047 vs 0.124 +/- 0.013 g/100 g body weight, P = .0001). Centrilobular hepatic congestion was present in all PAC rats and total hepatic oxygen delivery was reduced significantly compared to controls (146 +/- 58 mumols/min vs. 206 +/- 28 mumol/min; P = .025). In the PAC group, theophylline clearance was reduced (0.82 +/- 0.12 ml/min vs. 0.96 +/- 0.13 ml/min in controls; P = .014), and there was a nonlinear correlation between theophylline clearance and total hepatic oxygen delivery (r = .82). These results suggest that in animals with PAC, metabolism of theophylline was impaired as a result of a reduction in total hepatic oxygen delivery. Therefore, in addition to the known effect of reduced hepatic blood flow on the hepatic clearance of "flow limited" drugs, reduction of hepatic oxygen delivery may be another important mechanism that can lead to reduction in hepatic clearance of capacity-limited drugs in congestive heart failure.