The quantitation by gas chromatography-chemical ionisation-mass spectrometry of cyclophosphamide, phosphoramide mustard and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy

Jardine, I.; Fenselau, Catherine; Appler, Mark; Kan, Man-Na N.; Brundrett, Robert B.; Colvin, Michael

doi:10.1007/978-1-349-03328-7_8

Cited by 70 publications

(47 citation statements)

References 4 publications

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“…the plasma concentration range of 1-20 mg 1-'). This value is in approximate agreement with Jardine, Fenselau, Appler, Kan, Brundrett & Colvin (1978) who obtained a value of 24% in a single study, but greater than the 12-14% of Bagley, et al (1973).…”

Section: Resultssupporting

confidence: 92%

Repeated investigations of cyclophosphamide disposition in myeloma patients receiving intermittent chemotherapy.

Edwards¹,

Calvert²,

Crowther³

et al. 1980

Brit J Clinical Pharma

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Section: Resultssupporting

confidence: 92%

Repeated investigations of cyclophosphamide disposition in myeloma patients receiving intermittent chemotherapy.

Edwards¹,

Calvert²,

Crowther³

et al. 1980

Brit J Clinical Pharma

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“…Bagley et al (1973) found that 12-14% of radio-labelled cyclophosphamide was bound to plasma protein in samples from their patients. Jardine, Fenselau, Appler, Kan, Brundrett & Colvin (1978) however, found 24% cyclophosphamide binding in a single patient study. This was carried out at 4°C with frozen plasma samples which may explain the discrepancy of their findings.…”

Section: Discussionmentioning

confidence: 88%

The kinetics of salivary elimination of cyclophosphamide in man.

Juma¹,

Rogers²,

Trounce³

1979

Brit J Clinical Pharma

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1 The concentrations of cyclophosphamide in plasma and saliva were determined in seven patients following administration of single doses of cyclophosphamide during chemotherapy for lymphoma. 2 The saliva/plasma ratio was 0.77 +/‐ 0.24 (s.d.) and showed no time‐ dependence being rapidly established following intravenous and oral administration. 3 The T 1/2 of cyclophosphamide (8.38 +/‐ 2.25 h) determined from salivary measurements was not significantly different from that in plasma (8.24 +/‐ 2.60 h). It was not possible to estimate the apparent volume of distribution or total body clearance utilizing the salivary cyclophosphamide concentration without appropriate correction for the saliva/plasma concentration ratio. 4 The binding to the plasma protein of normal plasma of cyclophosphamide was 13.4 +/‐ 5.3%. The Scatchard plot for binding to bovine serum albumin indicates only weak binding to non‐specific sites. 5 Salivary cyclophosphamide therefore indicates the concentration of the unbound fraction of plasma cyclophosphamide.

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“…This may be the result of the affinity of acrolein for sulfhydryl groups including, possibly, the alkyl-accepting cysteine residue of the ATase protein. The peak concentration of phosphoramide mustard achieved in the serum following high dose cyclophosphamide (60 and 75 mg kg-') was 50-100 ILM (Colvin & Chabner, 1990;Jardine et al, 1978;Juma et al, 1979) indicating that the concentration of intracellular acrolein that depletes recombinant human ATase in vitro is potentially attainable in vivo. Phosphoramide mustard was also able to deplete ATase activity but the concentration required (>1 mM) was far in excess of that achievable in patients receiving the drug (Colvin & Chabner, 1990;Jardine et al, 1978;Sladek et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…There was progressive reduction in WBC counts over the 5-7 days of cyclophosphamide/BCNU and cyclophospha- (0) ing the drug (>1 mM) (Jardine et al, 1978;Sladek et al, 1984;Juma et al, 1979).…”

mentioning

confidence: 99%

Cyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation

Lee

Crowther²,

Scarffe³

et al. 1992

Br J Cancer

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Summary 06-alkylguanine-DNA-alkyltransferase (ATase) levels were measured in extracts of peripheral blood lymphocytes taken at various times during chemotherapy from 19 patients with various haematological malignancies. Seven patients with advanced Hodgkin's disease received preparative treatment consisting of cyclophosphamide (1.5 g m-2, daily) administered on days 1 to 4 and BCNU (600 mg m-2) on day 5 prior to autologous bone marrow rescue (ABMR) delivered on day 7. Treatment in the remaining 12 patients consisted of cyclophosphamide (1.8 g m2, daily) given on days 1 and 2 followed at day 4 with total body irradiation (TBI) administered in six fractions over the subsequent 3 days to a total dose of 1200 cGy prior to bone marrow transplantation. In the Hodgkin's group, significant decreases in ATase activity were seen during the cyclophosphamide treatment, and the median ATase nadir was 32% (range 0% to 57%) of pretreatment levels following 4 days of cyclophosphamide. In one patient, no ATase activity was detectable following the 4th cyclophosphamide treatment. ATase activities decreased further after BCNU administration to a median of 19% (range 0% to 32%) of pretreatment levels. Extensive cyclophosphamide-induced reduction of lymphocyte ATase levels was also seen in the other group of 12 patients treated with cyclophosphamide/TBI: postcyclophosphamide median ATase nadir was 35% (range 12% to 78%) of the pretreatment levels. No ATase depletion was seen when cyclophosphamide (up to 1O mM) was incubated for 2 h with pure recombinant human ATase in vitro whereas ATase activity was reduced by 90% on preincubation with 100 tsm acrolein or with > 1 mM phosphoramide mustard. This suggests that a cyclophosphamide-induced decrease in ATase levels in human peripheral lymphocytes in vivo may be due to depletion mediated by the production of intracellular acrolein. Since ATase appears to be a principal mechanism in cellular resistance to the cytotoxic effects of BCNU and related alkylating agents, these observations suggest that a cyclophosphamide-induced reduction in ATase activity may be an additional factor in the effectiveness of the combined sequential therapy.

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The quantitation by gas chromatography-chemical ionisation-mass spectrometry of cyclophosphamide, phosphoramide mustard and nornitrogen mustard in the plasma and urine of patients receiving cyclophosphamide therapy

Cited by 70 publications

References 4 publications

Repeated investigations of cyclophosphamide disposition in myeloma patients receiving intermittent chemotherapy.

Repeated investigations of cyclophosphamide disposition in myeloma patients receiving intermittent chemotherapy.

The kinetics of salivary elimination of cyclophosphamide in man.

Cyclophosphamide decreases O6-alkylguanine-DNA alkyltransferase activity in peripheral lymphocytes of patients undergoing bone marrow transplantation

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