SUMMARY BackgroundAcute severe ulcerative colitis (ASUC) is a potentially life-threatening complication of ulcerative colitis.

1. The disposition of warfarin enantiomers and metabolites has been studied in 36 patients receiving chronic rac‐warfarin therapy, titrated to approximately the same anticoagulant response. 2. A stereoselective h.p.l.c. assay was employed to determine the concentrations of (R)‐ and (S)‐warfarin, (R,S)‐warfarin alcohol and (S)‐7‐hydroxywarfarin in plasma and 24 h urine samples. The concentrations of (R)‐7‐ hydroxywarfarin, (S,S)‐warfarin alcohol and (R)‐6‐ and (S)‐6‐ hydroxywarfarin were also determined in urine samples. The fractions unbound of warfarin enantiomers were determined using equilibrium dialysis. 3. Wide variability was observed in daily dose requirements (mean 6.1 mg; range: 2.5‐12 mg), in plasma concentrations of (S)‐ warfarin (0.48 mg l(‐1); 0.11‐1.02 mg l(‐1)), (R)‐warfarin (0.87 mg l(‐ 1); 0.29‐1.82 mg l(‐1)), (R,S)‐warfarin alcohol (0.31 mg l(‐1); 0.02‐ 0.72 mg l(‐1)) and (S)‐7‐hydroxywarfarin (0.25 mg l(‐1); 0.07‐0.37 mg l(‐1)) and the percentage unbound of (S)‐warfarin (0.53%; 0.29%‐0.82%) and (R)‐warfarin (0.54%; 0.26%‐0.96%). 4. The mean plasma clearances of warfarin enantiomers were 7.5 1 day‐1 per 70 kg (2.5‐22.1) for (S)‐ warfarin and 3.6 1 day‐1 per 70 kg (1.6‐8.8) for (R)‐warfarin. There was a significant correlation between the estimated formation clearance of (S)‐7‐hydroxywarfarin and the clearance of (S)‐warfarin, which accounted for much of the variability in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

1 The population pharmacokinetics of fluconazole have been investigated in 113 male subjects with HIV infection and AIDS. Plasma concentration-time data ( between 1 and 17 observations per dose) were collected from individuals as part of a pharmacokinetic investigation ( 13 subjects) or during routine fluconazole therapy (100 subjects) for the treatment or prophylaxis of fungal infection. 2 A one-compartment pharmacokinetic model was used to describe the disposition of fluconazole after oral and intravenous infusion doses. Population pharmacokinetic parameters were generated using the NONMEM and P-PHARM computer programs. 3 The population estimates (calculated using NONMEM) of fluconazole clearance and volume of distribution were 0.78 l h−1 and 47.6 l, respectively. The intersubject variability for these parameters was 41% and 8%, respectively. The model-dependent estimate of the extent of absorption was 0.99 with an intersubject variability of 6%. Mean population estimates generated by NONMEM and P-PHARM were in close agreement. 4 Examination of the relationship between patient covariates and pharmacokinetic parameters indicated that intersubject variability in fluconazole clearance could in part be explained by the severity of disease (as indicated by CD4+T-lymphocyte count) and renal function (indicated by estimated creatinine clearance). Other pharmacokinetic parameters were unaffected by these covariates. 5 Fluconazole clearance (estimated using NONMEM) in subjects with a CD4+T-lymphocyte count less than and greater than 200 cells mm3 was 0.73 l h−1 (95% CI ; 0.64-0.82 l h−1) and 0.99 l h−1 ( 95% CI ; 0.86-1.12 l h−1), respectively. The regression model for fluconazole clearance that accounted for changes in renal function and disease severity was CL ( l h−1)=0.25 (33%)+0.0057 (32%)×CLcr (in ml min−1)+0.00068 ( 10%)×CD4 cell count (in cells mm−3) where intersubject variability (expressed as %CV ) is shown in brackets. 6 Based on pharmacokinetic considerations a reduction in the dose of fluconazole would appear to be warranted in people with HIV infection who are seriously ill or who have compromised renal function. However, the emergence of resistance to fluconazole must also be considered when thinking of dosage adjustments.

In eight patients with rheumatoid arthritis receiving racemic hydroxychloroquine, blood and urine concentrations of the enantiomers of hydroxychloroquine and its major metabolites were measured each month over the first 6 months of therapy. Plasma concentrations of hydroxychloroquine enantiomers were measured in five of these patients. In all patients, the blood concentration of (R)-hydroxychloroquine exceeded that of the (S)-enantiomer, the mean (R)/(S) ratio being 2.2 (range 1.6-2.9). A similar excess of (R)-hydroxychloroquine was found in the plasma, the mean (R)/(S) ratio being 1.6 (range 1.2-1.9). The mean enantiomer blood concentration ratio (R)/(S) for the metabolite desethylhydroxychloroquine was 0.45 (range 0.34-0.58) and for desethylchloroquine it was 0.56 (range 0.35-0.86) suggesting stereoselective metabolism of hydroxychloroquine. (S)-hydroxychloroquine had a mean (± s.d.) renal clearance from blood of 41 ± 11 ml min-', approximately twice that of (R)-hydroxychloroquine. The predicted unbound renal clearance was also higher for (S)-hydroxychloroquine. The clinical implications of enantioselective disposition of hydroxychloroquine are currently not known.

1 Eight healthy subjects received 50, 100, 300, 600 and 900 mg allopurinol daily for 1 week each, in random order with 1 week separating each treatment period. The pre-dose plasma concentration of oxypurinol, the extent of inhibition of xanthine oxidase, plasma urate concentration and urine urate excretion rate were assessed on the last 2 days of each treatment week. 2 The ratio of 1-methyluric acid ( 1MU) over 1-methylxanthine (1MX) in the urine, following a dose of 50 mg 1MX infused intravenously over 20 min, was used to measure the inhibition of xanthine oxidase. 3 The steady-state plasma concentration of oxypurinol increased linearly with increasing dose of allopurinol between 50 mg to 600 mg day−1, with a weak indication of saturation at the higher 900 mg day−1 dose rate. 4 The relationships between plasma oxypurinol concentration and xanthine oxidase inhibition ( 1MU/1MX ratio), plasma urate concentration and urine urate excretion rate were fitted to an inhibition sigmoid E max model and the C 50 values for oxypurinol were 26.38±4.87, (mean±s.d.) 36.58±8.36 and 24.61±9.08 m, respectively. 5 1MU/1MX ratio appeared to be a reliable index of xanthine oxidase activity in vivo as the C 50 for oxypurinol observed for 1MU/1MX ratio, plasma urate concentration and urine urate excretion rate were similar. 6 The concentration of oxypurinol required for inhibition of xanthine oxidase, as indicated by C 50 , was lower than those often observed in clinical practice.