1 Fifteen patients received 1.5 g m-2 of ifosfamide intravenously over 0.5 h every day for 5 days. Twenty-one courses of treatment were studied. Plasma was assayed for ifosfamide by gas liquid chromatography and plasma alkylating activity was measured using the nitrobenzylpyridine (NBP) reaction. 2 A pharmacokinetic analysis revealed a significant decrease in the median (range) elimination half-life of ifosfamide from 7.2 (2.8-14.2) h on day 1 to 4.6 (2.3-7.7) h on day 5 (P < 0.001, Wilcoxon's test) with a concomitant significant increase in the median (range) clearance from 66 (31-148) ml min-1 on day 1 to 115 (52-381) ml min-' on day 5 (P < 0.001). There was no significant change in the volume of distribution on day 5 compared with day 1.3 There was a highly significant 223% increase in the median (range) plasma nitrobenzylpyridine alkylating activity area under the curve on day 1 from 16 (0.6-105) nmol nor nitrogen mustard equivalents ml-' h to 52 (13-238) nmol nor nitrogen mustard equivalents ml-' h on day 5. 4 During five courses of treatment (in five patients in the group) 24 h urine samples were collected on days 1 and 5. The median (range) renal clearance of ifosfamide on day 1 was 6.8 (1.3-16.2) ml min-1 compared with 5.7 (1.3-15.3) ml min-1 on day 5. This difference was not significant. The median (range) metabolic clearance of ifosfamide in these five patients on day 1 was 78.6 (39.9-141.2) ml min-1 and 132.6 (54.6-149.5) ml min on day 5. This difference in metabolic clearance did not reach statistical significance. 5 These data indicate that after 5 days fractionated intravenous ifosfamide at 1.5 g m daily produces a time-dependent increase in ifosfamide metabolism.

1 We investigated the pharmacokinetics of ifosfamide 5 g m-2 given by two regimens.Six patients (one female), median age 55 (range 40-71) years, all with lung cancer received 5 g m-2 ifosfamide (median ifosfamide dose 8.95 g) as an intravenous infusion over 0.5 h with mesna. Four other cancer patients (all male) of median age 52.5 (range 23-72) years were studied on seven treatment occasions with 5 g m-2 ifosfamide (median ifosfamide dose 8.88 g) as a 24 h intravenous infusion with mesna. Plasma was assayed for ifosfamide by gas liquid chromatography and for alkylating activity by the nitrobenzylpyridine method. 2 After ifosfamide 5 g m-2 infused over 0.5 h, the decay of the plasma ifosfamide concentration was monoexponential with a median (range) t/2,z of 5.4 h (3.6-10.4 h).The median clearance was 60 ml min-1 (47-104) and the median volume of distribution was 388 (329-783) ml kg-'. Plasma nitrobenzylpyridine alkylating activity showed a biexponential decay in four patients and a monoexponential decay in two, with a median AUC of 102 (24-177) nmol nor nitrogen mustard eq h ml-'.3 When ifosfamide 5 g m-2 was given as a 24 h infusion, the decay of the plasma ifosfamide concentration was monoexponential, the median (range) t/2,z was 4.5 (3.4-6.1), the median volume of distribution was 563 (292-818) ml kg-1 and the median clearance was 79 (59-116) ml min-1. Plasma nitrobenzylpyridine alkylating activity decayed monoexponentially and the median AUC was 49 (45-131) nmol nor nitrogen mustard eq ml-' h.4 There was no evidence of saturation kinetics after high doses of ifosfamide. The clearance of ifosfamide at 5 g m-2 was similar whether it was given by short or 24 h intravenous infusion and was comparable with that observed after low doses of ifosfamide.

Hepatic N-acetylation phenotype has been suggested to be an important risk factor in the aetiology of bladder cancer. This study explores the N-acetylation capacity of a series of lung cancer cases (126) and two control groups. No overall association of slow or rapid acetylators exists between cancer patients and controls. There is also no difference in the distribution of acetylation phenotypes amongst the histological subtypes.