The effect of cirrhosis on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 15 healthy controls and eight patients with cirrhosis. The elimination half-life was prolonged from 5.2 +/- 2.4 hr (mean +/- SD) in controls to 6.1 +/- 1.9 hr in cirrhotics, although this did not reach statistical significance. The plasma clearance, however, was significantly higher (1.4 +/- 0.5 ml/min/kg) in controls as compared to cirrhotics (0.9 +/- 0.3 ml/min/kg) (P less than 0.05). The plasma binding of caffeine was also lower in cirrhotics (31.3 +/- 1.8% vs 25.5 +/- 4.0%, P less than 0.01). The plasma clearance of unbound caffeine therefore was reduced from 2.0 +/- 0.7 ml/min/kg in controls to 1.2 +/- 0.4 ml/min/kg (P less than 0.01) in cirrhotics, demonstrating impaired elimination of caffeine in cirrhosis.

The effects of acute and chronic maternal ethanol consumption on in vitro placental uptake of alpha-aminoisobutyric acid (AIB), cycloleucine, L-alanine (Ala), L-leucine (Leu), and L-lysine (Lys) were determined. Ethanol (4 g/kg. po) administered 2 hr prior to sacrifice, reduced (p less than 0.05) placental villous net uptake of cycloleucine and Ala by 29%. Prior chronic ethanol consumption depressed (p less than 0.05) placental uptake of AIB (38%), cycloleucine (45%), Ala (35%), Leu (25%), and Lys (34%). In vitro exposure of previously untreated villous fragments for 2 hr to 2 mg/ml of ethanol reduced (p less than 0.05) the net uptake of AIB and cycloleucine by 24% and 31%, respectively, whereas the minimum concentration of acetaldehyde required to cause a significant inhibition was 310 microM for AIB and 465 microM for cycloleucine. Ethanol (3 mg/ml) had no effect on AIB or cycloleucine net uptake if sodium was omitted from the incubation media. The efflux of AIB (10(-6)M) and cycloleucine (10(-6)M) from villous tissue was unaffected (p less than 0.05) by either ethanol (3 mg/ml) or acetaldehyde (600 microM) and obeyed first order kinetics. It was concluded that acute, and especially chronic, maternal ethanol consumption can depress the placental uptake of a variety of amino acids in the rat and, in the acute setting, the effect was on a sodium-dependent system involved in amino acid influx into placental cells.

We have studied chlordiazepoxide (Librium) disposition and elimination in eight normal subjects before and after 1 week of cimetidine therapy, 300 mg orally four times a day. Cimetidine strikingly impaired the clearance of chlordiazepoxide from plasma, and this was, at least in part, due to decreased demethylation of the drug to N-desmethylchlordiazepoxide. Since the volume of distribution of chlordiazepoxide was not altered by cimetidine, the elimination half-life of chlordiazepoxide was also significantly prolonged by cimetidine therapy.

Furosemide disposition after rapid intravenous injection (80 mg) was studied in 10 normal healthy subjects and eight patients with cirrhosis and ascites. In the cirrhotic patients the elimination half-life was modestly longer (81.0 +/- 8.0 min and 60.2 +/- 5.8 min). This prolongation was not associated with a difference in systemic clearance (156 +/- 7 ml/min in normal and 142 +/- 16 ml/min in cirrhotic subjects), rather it was a reflection of alterations in furosemide distribution. The steady-state volume of distribution was increased from 8.5 +/- 0.4 l in the healthy subjects to 12.1 +/- 1.3 l in the cirrhotic subjects; estimation in terms of unbound drug indicated an approximately 50% smaller value in cirrhosis. These observations were quantitatively consistent with the increased percentage of furosemide in plasma in the unbound form in the patients (10.2 +/- 1.0%) compared to in the normal subjects (4.0 +/- 0.1%). The 24-hr percentage urinary recovery of unchanged drug (58.8 +/- 2.8% and 53.1 6.5%) and the glucuronide metabolite (17.8 +/- 1.5 and 21.3 +/- 3.4) were on the same order in the normal and cirrhotic groups. The lack of major effects of cirrhosis on furosemide disposition suggests that changes in furosemide diuretic efficacy in such patients is a result of altered dynamic factors rather than altered disposition.