Hj Rogers

Effect of renal insufficiency on the pharmacokinetics of cyclophosphamide and some of its metabolites

SummaryCyclophosphamide 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. Vdβ, Vdss and Vc were not significantly different between the two groups. A linear relationship exists between β, 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 nitrobenzylpyridine 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.

Pharmacokinetics of intravenous cyclophosphamide in man, estimated by gas-liquid chromatography.

SummaryA 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.

Plasma and salivary pharmacokinetics of dapsone estimated by a thin layer chromatographic method

SummaryA high performance thin layer chromatographic assay for dapsone is described with a minimum level of detection of 20 ng ml−1 which is suitable for the study of dapsone pharmacokinetics in plasma and saliva. 100 mg dapsone was administered orally to seven normal adult volunteers, the mean plasma pharmacokinetic parameters were: α=0.23 h−1; β=0.0236 h−1, and t1/2β=30.2 h. Dapsone is also eliminated into the saliva and the t1/2 may be determined via its estimation in saliva. It is 73% bound to plasma protein and the saliva/plasma concentration ratio was found to be 27%. In two subjects the free plasma dapsone concentration was identical to the simultaneous salivary dapsone concentration. Therefore the salivary dapsone concentration is a measure of the free plasma fraction of dapsone. Saliva/plasma dapsone concentration ratios show no time or concentration dependence and little inter-individual variation but are unsuitable for acetylator phenotype determination because monoacetyldapsone is not eliminated in the saliva.

Pharmacokinetics of melphalan in children following high-dose intravenous injection.

SummaryThe pharmacokinetics of high-dose IV melphalan (140 or 220 mg m-2) were studied after 12 administrations in 10 children (aged 2.5–16 years) undergoing chemotherapy for either neuroblastoma or Ewings tumour. To assess whether a simpler and less expensive nitrobenzylpyridine (NBP) spectrophotometric assay for alkylating activity was a satisfactory alternative to high-pressure liquid chromatography (HPLC), the plasma melphalan concentration was estimated by both methods in five cases.Analysis of the disposition of melphalan gave a mean half-life of 1.3±1.0 (SD) h, clearance 18.4±9.4l · h1 · m2, and apparent volume of distribution 26.3±18.0 l · m-2. These pharmacokinetic parameters were similar to those found in adults: no correlation was found between any parameter and age or glomerular filtration rate.NBP alkylating activity determinations yielded consistent results and good correlation with plasma melphalan concentration. However, concordance analysis indicated a consistent bias, the NBP assay always giving lower estimates of plasma melphalan concentration: HPLC assay therefore remains the method of choice for determining plasma melphalan pharmacokinetics.

Pharmacokinetics of intravenous glibenclamide investigated by a high performance liquid chromatographic assay.

SummaryA simple high performance liquid Chromatographic assay for the determination of plasma glibenclamide concentrations is described. This resolved glibenclamide from normal plasma constituents. The calibration curve of the assay was linear over the range 10–500 μg/1 and the minimum level of detection was 2 μg/1. Within-assay coefficients of variation were 11.6% (20 μg/1); 5.3% (50 μg/1); 6.8% (100 μg/1); between-assay coefficients of variation were 8.4% (20 μg/1); 4.7% (50 μg/1) and 7.4% (100 μg/1). The assay was used to study the pharmacokinetics of a 1 mg intravenous dose of glibenclamide in eight normal subjects. The mean half-life was found to be 1.47±0.42 h (SD) and no evidence for a non-linear β-phase or slowly equilibrating ‘deep’ compartment was found although this could not be rigorously excluded. The mean systemic drug clearance was 78±29 ml·h-1·kg-1 and the apparent volume of distribution in the β-phase was 155±44 ml/kg. The median time of maximum response of plasma immunoreactive insulin was 25 min and the median time of maximum blood glucose response was 53 min. No correlation could be found between the pharmacokinetics of glibenclamide and these responses in fasted normal individuals.

Phase II trial of idarubicin in patients with advanced lymphoma

SummaryA phase II trial of idarubicin was performed in 24 patients with advanced lymphoma. The drug was administered in a dose of 10–15 mg/m2 i.v. or 15–70 mg/m2 p.o. (single dose) every 3 weeks. There were four partial responses and four minor responses. All but one of the responders had received prior doxorubicin therapy. The toxicities were myelosuppression, nausea and vomiting, and alopecia. Two patients with compromised cardiac function were observed to have further deterioration in the ejection fraction as measured by gated cardiac scan after idarubicin therapy. Further assessment of the activity of idarubicin against lymphoma is recommended in less heavily pretreated patients. The cardiac toxicity should be carefully monitored in future studies.

Plasma melphalan and prednisolone concentrations during oral therapy for multiple myeloma

SummaryNine patients with myeloma were studied over 13 oral administrations of 10 mg melphalan and 5–10 mg prednisolone. Plasma melphalan concentrations were estimated by high-pressure liquid chromatography, prednisolone concentrations by quantitative thin-layer chromatography. The mean plasma half-life of unchanged melphalan was 0.9±0.5 (SD) h. The ‘lag-time’ before melphalan was detected in the plasma varied from 1 to 4 h, the mean peak concentration was 96±21 ng/ml, and the mean area under the plasma concentration by time curve was 160±78 ng h/ml. This variability was consistent with observations made elsewhere following much higher oral doses of melphalan and illustrates the relatively wide interindividual variability of absorption. Observations made in the same subjects on two separate occasions showed lower variability. The melphalan elimination rate was not significantly affected by moderate impairment of creatinine clearance (to 31 ml/min). Absorption of prednisolone in five of these patients was apparently normal and unaffected by concurrent administration of melphalan.

Uroepithelial and nephrotubula toxicity in patients receiving ifosfamide/mesna: Measurement of urinary N-acetyl-β-d-glucosaminidase and β-2-microglobulin

Abstract The effect of three ifosfamide/mesna regimens on urinary N -acetyl-β- d -glucosaminidase (NAG) activity and β-2-microglobulin (β 2 M) was studied. All regimens produced significant increases in these urinary proteins, indicating nephrotubular damage. In regimen A ( n = 15), plasma nitrobenzylpyridine (NBP) alkylating activity area under the curve (AUC) on day 1 correlated with the percentage increase above baseline of maximum urinary NAG activity ( r 2 = 0.538, P = 0.0022) and maximum β 2 M concentration ( r 2 = 0.413, P = 0.0097). In regimen B ( n = 5), plasma NBP alkylating activity AUC correlated with the percentage increase above baseline of maximum NAG activity ( r 2 = 0.843, P = 0.03) and β 2 M ( r 2 = 0.78, P = 0.046). In these two regimens the renal exposure to ifosfamide metabolites correlated with the increases in urinary NAG and β 2 M. The relation of these urinary protein abnormalities to longer term effects on renal function with different ifosfamide/mesna schedules requires further study.

Acetylation and oxidation phenotypes in malignant lymphoma

Summary101 white British adults with Hodgkins disease or non-Hodgkins lymphoma were phenotyped for acetylation status using dapsone and for oxidation status with debrisoquine prior to treatment. The frequencies of acetylation and oxidation phenotypes in these patients were compared with reference populations of normal subjects. No significant difference in phenotype frequency was found in the lymphoma patients. This suggests that neither of these metabolic polymorphisms for exogenous compounds is strongly associated with these malignancies. Owing to the small size of the study, however, an effect of these phenotypes could not be excluded.

Biliary elimination of cyclophosphamide in man

SummaryA 72-year-old male with a lymphoma and obstructive jaundice received 900 mg cyclophosphamide IV as a part of a chemotherapeutic regimen whilst external biliary drainage was in progress. Plasma, urinary, and biliary pharmacokinetics of cyclophosphamide and nitrobenzylpyridine (NBP)-alkylating metabolites were studied. In 32 h 891 ml bile was collected, and this contained unchanged cyclophosphamide and NBP-alkylating material. Despite fluctuations in biliary flow, estimates of the half-life of cyclophosphamide from plasma, urine, and bile were similar. Good correlation existed between plasma and biliary cyclophosphamide concentrations after the initial plasma had been completed. The ratio of bile to plasma concentrations was 0.7 and showed no time dependence, as evidenced by a lack of hysteresis in the correlation curve. Of the administered dose, 3.5% was excreted as unchanged cyclophosphamide in the bile over 32 h. NBP-alkylating activity was found in bile up to 25 h but not after this time, despite the presence of unchanged cyclophosphamide in plasma. NBP-alkylating material was not found in the bile when it could not be detected in plasma, and vice versa.