Comparative study on human pharmacokinetics of activated ifosfamide and cyclophosphamide by a modified fluorometric test

Wagner, Th.; Heydrich, D.; Jork, T.; Voelcker, Georg; Hohorst, H. J.

doi:10.1007/bf00405906

Cited by 69 publications

(30 citation statements)

References 7 publications

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“…urinary concentrations of 4-OH-IF of up to 30 pmol/l were detected [37]: however, these results can not be compared directly with the situation in children receiv ing chemotherapy because the doses applied are higher, and continuous infusions of IF with simultaneous forced diuresis over several days are used. Moreover, no information is available regarding the concentrations of 4-OH-IF in the primary filtrate which the apical membrane of the renal tubule is exposed to or in the interstitial fluid.…”

Section: Discussionmentioning

confidence: 88%

Effect of Ifosfamide Metabolites on Sodium-Dependent Phosphate Transport in a Model of Proximal Tubular Cells (LLC-PK<sub>1</sub>) in Culture

Mohrmann¹,

Pauli²,

Walkenhorst³

et al. 1993

Kidney Blood Press Res

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Ifosfamide (IF) is an alkylating cytostatic drug with urotoxic (hemorrhagic cystitis) and nephrotoxic side effects. Several cases of Fanconi syndrome in children following therapy with IF were reported. Little information is available concerning the pathomechanisms of transport inhibition by IF. We used a permanent renal epithelial cell line with proximal tubular characteristics (LLC-PK₁) in order to investigate the effects of IF and some of its major metabolites (4-OH-IF, chloracetaldehyde, and acrolein). LLC-PK₁ cells were used in a confluent state. Sodium-dependent and sodium-independent fluxes of ³²PO₄ were determined by standard techniques. Activities of marker enzymes of apical and basolateral membranes, of mitochondria, and of endoplasmic reticulum were determined in cell homogenates. IF induces a moderate stimulation of PO₄ transport. 4-OH-IF also has a stimulatory effect on transport at low concentrations (up to 200 µmol/ l) and with short incubation (2h), while a 24-hour exposure of cells to 100 µmol/l of 4-OH-IF has an inhibitory effect of PO₄ transport. Concentrations of 4-OH-IF which inhibit transport also reduce the activity of Na⁺-K⁺-ATPase. Chloracetaldehyde, like 4-OH-IF, induces a biphasic response of PO₄ transport with stimulation in the low concentration range (up to 75 µmol/l) and inhibition at higher concentrations. Chloracetaldehyde reduces the activity of succinate-cytochrome coxidoreductase, suggesting that a defect in ATP generation might play a role in the pathogenesis of Fanconi syndrome induced by IF. Acrolein strongly damages monolayers and reduces sodium-dependent transport of P0₄ to very low levels at 150 µmol/l. It reduces the activities of both Na⁺-K⁺ ATPase and succinate-cytochrome c oxidoreductase. Acrolein also is the only metabolite with a moderate effect on alkaline phosphatase. We conclude that sodium-dependent transport of PO₄ is highly sensitive to IF metabolites. In addition to direct toxic effects of IF metabolites on transport proteins within the apical plasma membrane, damage to mitochondrial enzymes and to Na⁺-K⁺ ATPase which generates the electrochemical gradients for secondary active PO₄ transport may play an important role in the pathogenesis of Fanconi syndrome induced by IF.

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Section: Discussionmentioning

confidence: 88%

Effect of Ifosfamide Metabolites on Sodium-Dependent Phosphate Transport in a Model of Proximal Tubular Cells (LLC-PK<sub>1</sub>) in Culture

Mohrmann¹,

Pauli²,

Walkenhorst³

et al. 1993

Kidney Blood Press Res

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“…Thus, a prolongation in cyclophosphamide elimination half-life will result in a prolongation of the apparent half-life of phosphoramide mustard and probably more importantly that of 4-hydroxycyclophosphamide. Wagner et al (1981) has shown that the apparent half-life of 4-hydroxyifosfamide is approximately 6 h and it would therefore seem likely that the half-life of this metabolite is dependent on the half-life of the parent drug. Thus alteration of the elimination of the half-life of ifosfamide with age may alter the plasma concentration-time profile of the principal metabolite 4-hydroxyifosfamide.…”

Section: Discussionmentioning

confidence: 99%

The effect of age on the pharmacokinetics of ifosfamide.

Lind

Margison

Cerny

et al. 1990

Brit J Clinical Pharma

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The effect of age on the pharmacokinetics of ifosfamide was studied in 20 patients with advanced non small cell lung cancer. A positive correlation was found between the elimination half-life of ifosfamide and age (r = 0.48, 0.05 < P < 0.01). This was due to an increase in volume of distribution with age (r = 0.66, 0.001 < P < 0.01). Total plasma clearance, renal clearance and non renal clearance did not change with age. Age did not affect the autoinduction of ifosfamide metabolism. Further studies are needed to demonstrate any adverse effects of ifosfamide in the elderly.

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“…IF and its metabolites are usually determined by classical techniques (fluorimetry, mass spectrometry, chromatography) on derivatized tissue extracts or body fluids (Wagner et al, 1981;Lind et al, 1989;Boddy et al, 1993). More recently however, 31P-MRS has also been used in vitro to follow the metabolism of two other oxazaphosphorine cytostatics, cyclophosphamide and mafosfamide, in cultured tumour cells (Boyd et al, 1980;Sonawat et al, 1990) and to analyse IF metabolities in body fluids from patients Gilard et al, 1993).…”

mentioning

confidence: 99%

In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas

Rodrigues

Maxwell²,

McSheehy³

et al. 1997

Br J Cancer

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SummaryThe direct detection and monitoring of anti-cancer drugs in vivo by magnetic resonance spectroscopy (MRS) may lead to improved anti-cancer strategies. 31P-MRS has been used to detect and quantify ifosfamide (IF) in vivo in GH3 prolactinomas and N-methyl-Nnitrosourea (MNU)-induced mammary tumours in rats. The average concentration of IF in the GH3 prolactinoma over the first 2 h following a dose of 250 mg kg-' i.v. was calculated to be 0.42 ,umol g-1 wet weight, with a half-life of elimination (t,,2) of 2-4 h. Carbogen (95% oxygen/5% carbon dioxide) breathing increased the amount of IF taken up by the GH3 prolactinoma by 50% (P<0.01) to 0.68 ,umol g-1 wet weight, although t,,2 elimination rates were unchanged. IF was also detected in the liver in vivo, with a t,,c of about 1 h. Carbogen breathing did not affect the maximum peak area (Cmax) or the t,,2 in the liver. Most importantly, the carbogen-induced increase in IF uptake by the tumour caused significant growth delay at all time points in the GH3 tumour growth between day 5 and day 12 (P < 0.01) compared with IF alone. These findings show that carbogen breathing has potential for increasing the efficacy of anti-cancer drugs. Isolated GH3 cells were sensitive to the parent drug (IF) in vitro (C~50 = 1.3 ± 0.2 mM) suggesting that the GH3 cells may be either expressing P450 enzymes or are sensitive to the parent drug per se.

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Comparative study on human pharmacokinetics of activated ifosfamide and cyclophosphamide by a modified fluorometric test

Cited by 69 publications

References 7 publications

Effect of Ifosfamide Metabolites on Sodium-Dependent Phosphate Transport in a Model of Proximal Tubular Cells (LLC-PK<sub>1</sub>) in Culture

Effect of Ifosfamide Metabolites on Sodium-Dependent Phosphate Transport in a Model of Proximal Tubular Cells (LLC-PK<sub>1</sub>) in Culture

The effect of age on the pharmacokinetics of ifosfamide.

In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas

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