Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration.

Juma, Francis D.; Rogers, H. J.; Trounce, J R

doi:10.1111/j.1365-2125.1979.tb01004.x

Cited by 102 publications

(48 citation statements)

References 16 publications

(15 reference statements)

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“…The ratio of cyclophosphamide concentrations between plasma and saliva is rapidly established and shows no time dependency. This is in contrast to the situation which obtains for procainamide (Galeazzi et al, 1976), theophylline (Koysooko, Ellis & Levy, 1974) and caffeine (Newton, Lind, Morrison, Rogers & Bradbrook, unpublished observations) but is consistent with our previous pharmacokinetic studies of cyclophosphamide which indicate a relatively rapid transfer of drug between peripheral and central compartments (Juma et al, 1979).…”

Section: Discussioncontrasting

confidence: 55%

“…Cyclophosphamide has previously been identified using mass-spectrometry in samples of human saliva by Duncan, Colvin & Fenselau (1973). It was therefore thought worthwhile to determine whether saliva could be used instead of plasma sampling to follow the kinetics of cyclophosphamide and thereby reveal the variability in drug disposition which is known to occur between patients (Bagley, Bostick, & De Vita, 1973;Juma, Rogers & Trounce, 1979 Preliminary experiments indicated that cyclophosphamide concentrations are unchanged in these fluids for at least 2 months under such conditions. Plasma and salivary cyclophosphamide concentrations were estimated by synthesis of the trifluoracetyl derivative and subjecting this to gas-chromatography using alkali flame ionization detection according to the procedure of Juma, Rogers, Trounce & Bradbrook (1978).…”

Section: Introductionmentioning

confidence: 99%

“…Preliminary experiments having shown that cyclophosphamide is not bound to these membranes, ultrafiltration was then carried out by gentle centrifugation at 500g at 37°C until less than 5% of the fluid contained in the cones had been filtered. Cyclophosphamide levels were then estimated in the filtrate and the plasma by gas ©) Macmillan Journals Ltd. Juma et al (1979) using the simplex non-linear least squares digital computer program of Nelder & Mead (1965).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The kinetics of salivary elimination of cyclophosphamide in man.

Juma¹,

Rogers²,

Trounce³

1979

Brit J Clinical Pharma

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“…It is only recently that more interest has been placed on the pharmacokinetics of CP in high-dose therapy. 13,14 While the ␤-phase half-life (t 1/2␤ ) of CP obtained in this study is consistent with values reported previously, [15][16][17][18][19] the value of the ␤-phase volume of distribution (V t ) in this study was somewhat larger than those previously reported for the volume of distribution in humans, 20 which resulted in a markedly larger total clearance (CL) of CP as compared to that reported by other investigators. 16,19,21 It should be noted that when a similarly higher dose of CP was used, the volume of distribution at steady state (V ss ) (ie, 30.20 l) 12 was somewhat close to the value of V ss calculated in this study (ie 39.23 l).…”

Section: Tablesupporting

confidence: 58%

Urinary excretion and pharmacokinetics of acrolein and its parent drug cyclophosphamide in bone marrow transplant patients

Al‐Rawithi

El-Yazigi

Ernst

et al. 1998

Bone Marrow Transplant

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Summary:The urinary excretion and pharmacokinetics of acrolein (ACRO) and its parent drug cyclophosphamide (CP) were investigated in 16 randomly selected bone marrow transplant (BMT) recipients when CP was used for conditioning. Patients suffering from aplastic anemia (n = 3) received a 4-day course of CP at a dose of 50 mg/kg daily infused intravenously (i.v.) over 1 h. Patients with leukemia (n = 13) were given either a combination of busulphan followed by CP at a dose of 50 mg/kg infused i.v. over 1 h for 4 days, or CP at a dose of 60 mg/kg by i.v. infusion over 1 h daily for 2 days followed by total body irradiation. Serial plasma samples and urine were collected after the start of the first CP dose. CP was analyzed by capillary gas chromatography, whereas ACRO was measured in urine by Cyclophosphamide (CP) is an alkylating agent which requires metabolic activation to exhibit its antineoplastic and immunomodulating activities. Some of the metabolites formed are thought to cross-link with cellular DNA and thereby interfere with proliferation and ultimately lead to cell death. In bone marrow transplantation (BMT), CP is currently playing a major role as part of conditioning regimens. This treatment allows acceptance of the graft in allogenic BMT and serves in allo-as well as autologous BMT to eradicate malignant cells or create space in the marrow cavity. CP undergoes complicated metabolism involving several pathways in vivo. 1 The main pathway involves hydroxylation of CP by hepatic microsomal oxidases to form 4-hydroxy-cyclophosphamide (4OH-CP) which is in equilibrium with its acyclic tautomeric form, aldophosphamide (ALDO). These metabolites are transport forms of CP. Oxidation of ALDO by aldehyde dehydrogenase results in the noncytotoxic metabolite carboxyphosphamide. Dehydrogenation of 4OH-CP gives another inactive metabolite, 4-keto cyclophosphamide. The final stage of activation, which takes place in cells that are susceptible, involves cleavage of 4OH-CP/ALDO by a ␤-elimination reaction to yield phosphoramide mustard and ACRO both of which are highly cytotoxic and represent active forms of the drug. One of the major dose-limiting side-effects of CP is hemorrhagic cystitis (HC) 2 which has been attributed to the urinary excretion of its metabolites, particularly ACRO. [3][4][5] Hemorrhagic cystitis which occurs in a somewhat unpredictable way, may be the result of altered pharmacokinetics of CP or elevated formation and/or variation in the renal excretion of ACRO. It may also be ascribed to inadequate urinary concentration of mesna, 5 a uroprotective agent used for neutralizing the damaging effect of ACRO by chelation.This study was undertaken to investigate the urinary excretion and pharmacokinetics of ACRO and its parent drug CP in BMT recipients when CP is used for conditioning, and to examine the relationship between hemorrhagic cystitis and urinary excretion of ACRO. Patients and methods Patient selectionA total of 16 patients ranging in age between 14 and 46 years were randomly selected among the ...

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“…The modified nitrobenzylpyridine (NBP) assay described by Juma et al (1979) was used. The intra-assay coefficient of variation was 9.6% at 2 nmol of nor nitrogen mustard ml-' and 5.8% at 30 nmol of nor nitrogen mustard ml-'.…”

Section: Measurement Ofplasma Nbp Alkylating Activitymentioning

confidence: 99%

The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.

Lewis

Fitzgerald

Mohan

et al. 1991

Brit J Clinical Pharma

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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.

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Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration.

Cited by 102 publications

References 16 publications

The kinetics of salivary elimination of cyclophosphamide in man.

The kinetics of salivary elimination of cyclophosphamide in man.

Urinary excretion and pharmacokinetics of acrolein and its parent drug cyclophosphamide in bone marrow transplant patients

The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.

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