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Cyclophosphamide pharmacokinetics were studied in seven patients with moderate to severe renal insufficiency (creatinine clearances 0-51 ml . min-1), and compared with a matched control group of patients with normal renal function. The mean half-life of cyclophosphamide following intravenous administration in the normal group was 8.21 +/- 2.33 (SD) h whilst that in renal failure was 10.15 +/- 1.80 h: these were significantly different. The total body clearance in the normal control group was 58.6 +/- 10.9 ml . kg-1h-1 which was significantly larger than in renal failure where it was 48.8 +/- 10.9 ml . kg-1h-1. Vd beta, Vdss and Vc were not significantly different between the two groups. A linear relationship exists between beta, the first order disposition rate constant and endogenous creatinine clearance since this drug shows a relatively small degree of compartmentalisation. The plasma half-life of phosphoramide mustard, a cytotoxic metabolite of cyclophosphamide, shows a parallel and significant increase in renal failure with the parent compound. The t1/2 in normal patients was 8.33 +/- 2.0 h, whilst in the renal failure group it was 13.37 +/- 4.23 h. Total alkylating activity as measured by the nitrobenzyl-pyridine reaction showed a significant increase in renal failure. This data suggests that in pharmacokinetic terms it may not be necessary to alter the dose of cyclophosphamide until there is severe renal impairment. Further studies correlating the efficacy and toxicity of the drug with its pharmacokinetics in renal failure are necessary.

SUMMARY Plasma concentrations of propranolol and practolol were measured in patients with coeliac disease and normal subjects. The mean plasma propranolol concentration in the coeliac patients was higher throughout the period of study, the differences being significant at one, six, and eight hours. The plasma concentration profile of practolol in the coeliacs followed a similar pattern but lagged behind that of the normal subjects. A possible reason for these differences is an alteration in the rate of drug diffusion across the atrophic mucosa of the upper jejunum in coeliac disease. Analysis of the results of the propranolol study suggests that an increase in the rate of absorption combined with saturation of first pass extraction may account for the increased plasma concentrations of unchanged propranolol found in coeliac disease. These abnormalities of drug absorption do not appear to be related to the duration of treatment with a gluten free diet.Earlier studies (Parsons et al., 1974a; Parsons et al., 1974b;Parsons and Kaye, 1974) have demonstrated significant differences from normal in theplasmaconcentrations and urinary excretion of a number of drugs given to patients with coeliac disease. There are probably several factors responsible for the altered patterns of antibiotic absorption that we have previously demonstrated in this condition . One way of delineating the abnormality of drug absorption is to compare the plasma concentrations produced by chemically related compounds in coeliac disease with those produced by the same drugs in normal individuals. Underlying factors controlling the degree of drug absorption (Hogben et al., 1959;Brodie, 1964) may each be individually assessed by comparing related drugs that differ from one another by a single characteristic-for example, molecular weight, pKa, degree of lipid solubility. For these reasons, we decided to measure the plasma concentrations of propranolol and practolol, two drugs fulfilling these criteria.

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A simple gas chromatographic assay utilising alkali flame ionisation detection is described for the estimation of cyclophosphamide as its trifluoroacetate derivative from plasma. Examination of five patients following intravenous cyclophosphamide gave values of 8.9 h (SD 2.7) for the half-life and 0.061 liters/h/kg (SD 0.011) for whole-body clearance of the drug.

1 Simple, accurate and specific gas-chromatographic methods for the estimation of derivatized phosphoramide and non-nitrogen mustards utilizing alkali-flame ionization detection are described. 2 The pharmacokinetics in plasma of cyclophosphamide, phosphoramide mustard, nor-nitrogen mustard and nitrobenzyl pyridine alkylating activity were investigated following administration of cyclophosphamide by intravenous and oral routes to patients with malignant disease 3 The mean T1 for cyclophosphamide was 8.88 h (s.d. 1.25 h) and the apparent volume of distribution (Vdfl) was 0.74 1 kg-1 (s.d. 0.16 1 kg-1).4 The decline in plasma concentration of phosphoramide mustard was biphasic, the longer T, being 8.68 h (s.d. 2.50 h). This was not significantly different from that of cyclophosphamide. This could indicate that the true biological T, for phosphoramide mustard is identical with or shorter than that of cyclophosphamide. 5 The plasma concentrations of phosphoramide mustard following cyclophosphamide doses of known therapeutic efficacy are probably insufficient to produce important cytotoxic effects. This suggests that if phosphoramide mustard is the major alkylating metabolite derived from cyclophosphamide, it is transported in the blood in precursor form. 6 The mean plasma T1 of nor-nitrogen mustard was 3.31 h (s.d. 1.60 h) which was significantly different from that of cyclophosphamide. 7 The mean plasma T, of the nitrobenzylpyridine alkylating activity was 9.81 h (s.d. 4.18 h) and did not significantly differ from that of cyclophosphamide. Although the area under the plasma alkylating activity concentration, time curve is related to the T1 of cyclophosphamide, the alkylating activity does not reflect the concentrations of the two plasma metabolites measured.