1 The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10-360 ,g kg-' h-1). 2 The mean plasma clearance of morphine was significantly higher in children than neonates (25.7 and 4.7 ml min-' kg-', respectively) (P < 0.01). 3 All the neonates and children had detectable concentrations of morphine-3-glucuronide (M3G) in plasma. All the children and five neonates had detectable concentrations of morphine-6-glucuronide (M6G) in plasma or urine. 4 The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine were significantly higher in children than neonates (P < 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period. 5There was no difference in the M3G/M6G ratio in children and neonates, indicating a parallel development of both glucuronidation pathways.

1 The effect of low dose steady state warfarin (0.2 mg and 1 mg daily) on clotting factor activity and vitamin K1 metabolism was studied in seven healthy volunteers. 2 Steady state plasma warfarin concentrations were 41‐99 ng ml‐1 for the 0.2 mg dose and 157‐292 ng ml‐1 for the 1 mg dose. 3 There was a significant prolongation of the mean prothrombin time (0.9 s) after 1 mg warfarin daily, but no significant change in prothrombin time after 0.2 mg warfarin daily. There was no significant change in individual clotting factor activity (II, VII, IX or X) with either dose of warfarin. 4 Following the administration of a pharmacological dose of vitamin K1 (10 mg), all seven volunteers had detectable levels of vitamin K1 2,3‐epoxide with both doses of warfarin (Cpmax 31‐409 ng ml‐1). 5 Both the Cpmax and the AUC for vitamin K1 2,3‐ epoxide were significantly greater on 1 mg of warfarin daily than 0.2 mg daily (P less than 0.01). 6 The apparent dissociation between inhibition of vitamin K1 2,3‐epoxide reductase and reduction of clotting factor activity, produced by warfarin, may reflect the insensitivity of functional clotting factor assays to a small reduction in clotting factor concentration.

1 The stereoselectivity of the pharmacokinetic interaction between warfarin and cimetidine was investigated in eight healthy volunteers. 2 The warfarin enantiomers were given separately as single doses (15 mg) alone and during chronic administration of cimetidine (1 g day-1). 3 Cimetidine did not interact with S warfarin but there was an interaction with the R enantiomer of warfarin. Cimetidine caused a significant increase in the mean plasma halflife of R warfarin (from 47.8 h to 57.8 h) and a significant decrease in its mean plasma clearance (from 2.3 to 1.7 ml h-1 kg-') (P < 0.02). 4 Administration of a pharmacological dose of vitamin K1 together with the enantiomers of warfarin was necessary clinically and resulted in elevation of vitamin K1 2,3-epoxide concentrations, which were similar in each case.

The effect of the individual enantiomers of warfarin at steady state (lmg daily) was investigated in five healthy volunteers. Both enantiomers produced a significant increase in prothrombin time, but the increase with S warfarin (1.8 ± 0.8 s, mean ± s.d.) was greater than with R warfarin (1.0 ± 0.3 s), despite lower steady state plasma concentrations of S warfarin, due to its more rapid clearance. Following the administration of vitamin K1, the maximum plasma concentration and area under the plasma concentration time curve values for the metabolite vitamin K1 2,3-epoxide were greater after S warfarin than after R warfarin. The greater anticoagulant potency of S warfarin is reflected by a greater degree of inhibition of vitamin K1 epoxide reductase.

The metabolism of morphine was studied in seven fullterm neonates and five infants receiving a continuous infusion of morphine. All the patients had detectable plasma concentrations of morphine 3‐glucuronide (M3G) and 10 had detectable concentrations of morphine 6‐glucuronide (M6G). The mean plasma clearance of morphine was 20.1 ml min‐1 kg‐1 in neonates and 23.4 ml min‐1 kg‐1 in the group as a whole. The M3G/morphine ratio (7.3) was higher than that previously reported for preterm neonates (5.0) but lower than that reported for children (23.9).