John Feely

Reduction of Liver Blood Flow and Propranolol Metabolism by Cimetidine

We studied the influence of cimetidine on liver blood flow in eight normal subjects. Cimetidine acutely reduced liver blood flow during fasting by almost 25 per cent, as measured by indocyanine green clearance. Chronic cimetidine therapy (300 mg four times daily for seven days) reduced the flow by 33 per cent, as measured over eight hours by calculating the relative disposition of oral and intravenous propranolol. In addition to reducing the clearance of intravenous propranolol by decreasing live blood flow, cimetidine also inhibited the metabolism of oral propranolol and thereby further reduced elimination. The reduction in clearance of oral propranolol correlated positively (r = 0.87, P less than 0.05) with the average steady-state concentration of plasma cimetidine, suggesting that the inhibition of drug metabolism by cimetidine is dose related. Pulse rates at rest were markedly lower after propranolol plus cimetidine than after propranolol alone. The reduction in liver blood flow produced by cimetidine has important therapeutic implications for patients with alterations in liver and gastrointestinal blood flow and when drugs are used whose hepatic elimination depends on liver blood flow.

Increased Toxicity and Reduced Clearance of Lidocaine by Cimetidine

Cimetidine reduced liver blood flow and the systemic clearance of drugs, such as propranolol, that are highly extracted by the liver. In a randomized placebo-controlled study, we examined the influence of cimetidine, 300 mg four times daily for 1 d, on the disposition of lidocaine, 1 mg/kg body weight by a 10-minute intravenous infusion. Cimetidine reduced the systemic clearance of lidocaine from 766 +/- 50 mL/min to 576 +/- 47 mL/min (p less than 0.05); the apparent volume of distribution at steady-state and the degree of plasma protein binding of lidocaine also were decreased. Five of the six subjects noted lidocaine toxicity during the cimetidine infusion in contrast to one subject on the placebo day. The peak lidocaine concentration (mean +/- SE) was 50% +/- 10% higher when subjects received cimetidine. This study provides additional evidence that the effect of cimetidine on the elimination of other drugs has multiple factors, and shows a previously unrecognized mechanism, involving altered initial drug distribution, whereby the interaction of cimetidine with other drugs may cause toxicity.

Effect of Hypotension on Liver Blood Flow and Lidocaine Disposition

IN comparison to other highly vascular organs, the liver has a limited ability to autoregulate blood flow in the presence of hypotension.1 This may have important consequences for the clearance of ...

Reduction of liver plasma flow by caffeine and theophylline

Caffeine and theophylline block the vasodilating effects of adenosine and may act to enhance sympathoadrenal discharge and activate the renin‐angiotensin system. To determine if these methylxanthines might thereby have effects on regional blood flow, we studied the influence of caffeine and theophylline on apparent liver plasma flow (LPF) in normal subjects as assessed by indocyanine green clearance. Oral caffeine, 250 mg, reduced LPF by 19% from 630 ± 150 to 510 ± 120 ml/min (P < 0.001). Intravenous theophylline (4.3 mg/kg) reduced LPF by 15% from 550 ± 50 to 470 ± 90 ml/min (P < 0.05). These methylxanthine‐induced falls in LPF may alter the disposition of concomitantly administered drugs. Because of their widespread use in Western society, caffeine and theophylline may be major determinants of liver blood flow in the general population. They may therefore prolong the t1/2 and increase steady‐state levels of hepatically eliminated drugs.

Effect of thyrotoxicosis on liver blood flow and propranolol disposition after long-term dosing

The effects of thyrotoxicosis on liver blood flow and propranolol disposition were followed in five patients while thyrotoxic and when euthyroid. Propranolol was taken orally to achieve steady state and then radiolabeled drug was given simultaneously by intravenous injection. Thyrotoxicosis was associated with doubling of both oral and systemic clearances of unbound propranolol, which resulted in an approximately 50% reduction in blood concentrations after oral doses. These changes were attributable to increases in hepatic blood flow and drug‐metabolizing activity of the liver. The propranolol elimination t½ was not affected by thyrotoxicosis since the enhanced clearance was offset by a change in volume of distribution. These findings may explain the reduction of plasma propranolol concentration and many of the therapeutic failures reported in the treatment of thyrotoxicosis. The dose required to achieve therapeutic blood concentrations of propranolol in thyrotoxic patients is variable and will usually be substantially larger than that required for euthyroid patients.

Effect on apparent liver blood flow of histamine-receptor blockers and inhibition of prostaglandin synthesis

We have recently shown that histamine H2‐receptor blockade with Cimetidine reduces apparent liver blood flow. To determine the effects of inhibition of Prostaglandin synthesis and of H1‐receptor blockade and of their additive effects when combined with Cimetidine (600 mg), we estimated liver blood flow from the clearance of a single dose (0.5 mg/kg) of indocyanine green (ICG) in six healthy subjects after indomethacin (50 mg, three times during 24 hr) and chlorpheniramine (8 mg, three times during 24 hr). Indomethacin and chlorpheniramine reduced ICG estimated liver blood flow by 18 ± 3% and 13 ± 4% (mean ± SEM). When Cimetidine was added to indomethacin or chlor pheniramine, the reductions inflow of 22 ± 6% and 19 ± 5% were not significantly greater than that after indomethacin, chlorpheniramine, or Cimetidine alone (16 ± 6%). These data suggest that both histamine acting through H1‐ and H2‐receptors and Prostaglandins may influence liver blood flow in man and are consistent with evidence from animal experiments that suggest a role for Prostaglandins in H2‐mediated vascular responses.