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  • 1
    Electronic Resource
    Electronic Resource
    Cytochrome P-450IID6 phenotyping in cancer patients: debrisoquin and dextromethorphan as probes (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 125-128 
    Details
    ISSN: 1432-0843
    Keywords: Key words Cytochrome P-450IID6 ; Debrisoquine ; Dextromethorphan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The usefulness of substituting dextromethorphan for debrisoquin as a probe for cytochrome P-450IID6 deficiency was investigated in 20 male cancer patients. Each patient was studied on two occasions. An oral dose of dextromethorphan (60 mg) was administered to 13 patients and are week later an oral dose of debrisoquin (10 mg) was administered to each patient. The order was reversed for the other 7 patients. An 8-h urine sample was collected after administration of each test drug and assayed for parent drug and metabolites. Five poor metabolizers (PMs) and 15 extensive metabolizers (EMs) of debrisoquin were tested. The debrisoquin metabolic ratio (DMR), calculated as [parent drug]/[metabolite], correlated with the metabolic ratio of dextromethorphan (R 2=0.58, P=0.0001). All PMs of debrisoquin (metabolic ratio 〉12.0) were easily identified as being PMs of dextromethorphan (metabolic ratio 〉0.30). Within the EM group, there was a significant correlation between the metabolic ratios of debrisoquin and dextromethorphan (R 2=0.82, P〈0.0001). There was not as clear a correlation in the PM group (R 2=0.32, P=0.32). These findings suggest that dextromethorphan can be substituted for debrisoquin in establishing the debrisoquin phenotype in a patient population with metastatic cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689196
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  • 2
    Electronic Resource
    Electronic Resource
    The effects of cimetidine upon the plasma pharmacokinetics of doxorubicin in rabbits (1986)
    Springer
    Cancer chemotherapy and pharmacology 18 (1986), S. 219-222 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cimetidine is an H2 antagonist which inhibits cytochrome P-450 and reduces hepatic blood flow. To determine whether cimetidine interferes with the plasma pharmacokinetics of doxorubicin, we gave six female New Zealand rabbits doxorubicin 3 mg/kg, followed a month later by cimetidine 120 mg/kg every 12 h over 72 h and doxorubicin 3 mg/kg. Serial plasma specimens were obtained over 72 h and assayed for doxorubicin and its metabolites by high-performance liquid chromatography and fluorescence detection. Doxorubicin plasma pharmacokinetics were prolonged after cimetidine pretreatment [AUC 0.76±0.22 vs. 2.85±1.22 μM×h, no pretreatment vs pretreatment (p=0.005), half-life=11.7±6.55 vs 28.0±8.16 h (P=0.0002), and clearance=0.129±0.036 vs 0.036±0.0111/min-1 kg-1 (P=0.0007)]. No significant differences were found between the AUCs for doxorubicinol, 7-deoxy doxorubicinol aglycone, or two unidentified nonpolar metabolites in nonpretreatment and pretreatment studies. Cimetidine increases and prolongs the plasma exposure to doxorubicin in rabbits. Doxorubicin metabolism does not appear to be affected by cimetidine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00273389
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  • 3
    Electronic Resource
    Electronic Resource
    The effect of cimetidine on cyclophosphamide metabolism in rabbits (1990)
    Springer
    Cancer chemotherapy and pharmacology 27 (1990), S. 125-130 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Six female rabbits were given 20 mg/kg cyclophosphamide (containing 100 μCi [3H-chloroethyl]-cyclophosphamide) alone or 1 h following 100 mg/kg cimetidine. Serial plasma and urine specimens were collected and levels of cyclophosphamide and its metabolites (4-hydroxycyclophosphamide, 4-ketocyclophosphamide, phosphoramide mustard, and carboxyphosphamide) were measured. 4-Ketocyclophosphamide was the major metabolite present in rabbit plasma and urine, with lesser amounts of 4-hydroxycyclophosphamide, carboxyphosphamide, and phosphoramide mustard also being identified. Cimetidine pretreatment resulted in prolongation of cyclophosphamide's half-life from 24.3±7.3 to 33.5±9.5 min (mean ± SD;P=0.036) but did not significantly alter the AUC0–8 h for the latter drug. Cimetidine pretreatment resulted in a significantly greater AUC0–8 h for 4-hydroxycyclophosphamide (189.4±77 vs 364.6±126.7 μmol min/l−1;P=0.016) as compared with control values. A higher AUC0–8 h value for phosphoramide mustard (53.7±69.2 vs 95.7±34.7 μmol min/l−1) was also observed after cimetidine dosing but the difference was not significant (P=0.21). Kinetics of 4-ketocyclophosphamide and carboxyphosphamide were not significantly affected by cimetidine treatment. Cimetidine was added to hepatic microsomes isolated from phenobarbital-treated rabbits; it did not inhibit cyclophosphamide's metabolism in vitro, suggesting that its in vivo effect may be mediated through mechanisms other than cytochrome P-450 inhibition. Cimetidine pretreatment increases exposure to cyclophosphamide and its major activated metabolite, 4-hydroxycyclophosphamide. Potentiation rather than inhibition of cyclophosphamide's pharmacodynamic effect is to be predicted when cimetidine is given concomitantly with the former. Alterations in hepatic blood flow or mechanisms other than microsomal inhibition by cimetidine may explain this potentiation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689096
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Cytochrome P-450IID6 phenotyping in cancer patients: debrisoquin and dextromethorphan as probes (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 125-128 
    Details
    ISSN: 1432-0843
    Keywords: Cytochrome P-450IID6 ; Debrisoquine ; Dextromethorphan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The usefulness of substituting dextromethorphan for debrisoquin as a probe for cytochrome P450IID6 deficiency was investigated in 20 male cancer patients. Each patient was studied on two occasions. An oral dose of dextromethorphan (60 mg) was administered to 13 patients and are week later an oral dose of debrisoquin (10 mg) was administered to each patient. The order was reversed for the other 7 patients. An 8-h urine sample was collected after administration of each test drug and assayed for parent drug and metabolites. Five poor metabolizers (PMs) and 15 extensive metabolizers (EMs) of debrisoquin were tested. The debrisoquin metabolic ratio (DMR), calculated as [parent drug]/[metabolite], correlated with the metabolic ratio of dextromethorphan (R 2=0.58,P=0.0001). All PMs of debrisoquin (metabolic ratio 〉12.0) were easily identified as being PMs of dextromethorphan (metabolic ratio 〉0.30). Within the EM group, there was a significant correlation between the metabolic ratios of debrisoquin and dextromethorphan (R 2=0.82, P〈0.0001). There was not as clear a correlation in the PM group (R 2=0.32, P=0.32). These findings suggest that dextromethorphan can be substituted for debrisoquin in establishing the debrisoquin phenotype in a patient population with metastatic cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689196
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    Paper (German National Licenses)
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  • 5
    Electronic Resource
    Electronic Resource
    Treatment of poor-prognosis extensive disease small-cell lung cancer with an all-oral regimen of etoposide and cyclophosphamide – a Southwest Oncology Group clinical and pharmacokinetic study (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 461-468 
    Details
    ISSN: 1432-0843
    Keywords: Key words Etoposide ; Cyclophosphamide ; Oral chemotherapy ; Pharmacodynamics ; Small-cell lung cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: An all-oral regimen of etoposide and cyclophosphamide was developed for use in poor-prognosis extensive disease small-cell lung cancer. Limited pharmacokinetic sampling was used to derive a pharmacodynamic model predictive of myelosuppression early in the course of therapy. Patients and methods: Eligible patients were chemotherapy-naive and had extensive disease small-cell lung cancer with either SWOG performance status 2 or serum albumin 〈3.5 g/dl. The first cohort (n = 18) received etoposide orally at 50 mg daily and cyclophosphamide orally at 50 mg daily days 1–14 every 28 days. Due to good hematologic tolerance, the second cohort (n = 39) received both agents orally at 50 mg twice daily days 1–14 every 28 days. Plasma etoposide levels were determined in samples drawn at baseline, and at 1 h, 2 h, and 23.5 h (trough) after the first dose. Linear regression analysis was used to determine pharmacokinetic and demographic parameters predictive of myelosuppression. Results: A total of 173 treatment cycles were delivered. Patients on the daily regimen had a 22% response rate (complete and partial), a 22% unconfirmed response rate, and a 5-month median survival, while patients on the twice-daily regimen had a 28% response rate (complete and partial), a 13% unconfirmed response rate, and a 7-month median survival. Granulocytopenia and alopecia were the most common toxicities seen. Significant granulocytopenia could be predicted for the twice-daily regimen according to the formula ln(AGC nadir)=7.80 − 1.88(trough), with an increased incidence of granulocytopenia if the etoposide trough value was ≥1.49 μg/ml. Conclusion: Oral etoposide and oral cyclophosphamide given days 1–14 every 28 days is well tolerated and results in an acceptable response rate and median survival in poor-prognosis (poor performance status or low serum albumin) extensive disease small-cell lung cancer. A trough etoposide level obtained within 24 h of starting therapy can predict severe granulocytopenia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800051119
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  • 6
    Electronic Resource
    Electronic Resource
    The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin in rabbits (1988)
    Springer
    Cancer chemotherapy and pharmacology 21 (1988), S. 323-328 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The influence of ranitidine on the pharmacokinetics and toxicity of doxorubicin was studied in six female New Zealand white rabbits. Plasma pharmacokinetic data were first obtained from rabbits given 3 mg/kg doxorubicin. After 1 month, the same rabbits were treated with ranitidine, 2.5 mg/kg or 25 mg/kg, before and during doxorubicin administration. The plasma doxorubicin assays to determine pharmacokinetic parameters were repeated. Drug toxicity was evaluated using complete blood counts, and hepatic function was measured using a 14C-aminopyrine breath test. High-dose ranitidine increased the total exposure to doxorubicin (area under the curve of doxorubicin alone =1.44±0.88 μ M·h/ml vs 4.49±2.35 μM·hr/ml for doxorubicin given with high-dose ranitidine; P=0.06). Low-dose ranitidine did not alter doxorubicin pharmacokinetics. Exposure to doxorubicinol was altered by either high-dose or low-dose ranitidine. 14C-Aminopyrine half-life was altered by a raniditine dose of 25 mg/kg (aminopyrine half-life after placebo control =97±6 min as against aminopyrine half-life after ranitidine =121±7 min; mean±SEM; P〈0.02). Low-dose ranitidine did not exacerbate doxorubicin-induced myelosuppression. High-dose ranitidine enhanced doxorubicin-induced erythroid suppression while sparing the myeloid series. At cytochrome P-450-inhibitory doses, ranitidine's effects upon doxorubicin plasma pharmacokinetics are similar to those previously seen with cimetidine. These changes did not appear to alter drug detoxification and are not related to microsomal inhibition of doxorubicin detoxification. Low doses of ranitidine do not alter doxorubicin plasma pharmacokinetics or toxicity in rabbits.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00264199
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  • 7
    Electronic Resource
    Electronic Resource
    Improved high-performance liquid chromatography assay of doxorubicin: Detection of circulating aglycones in human plasma and comparison with thin-layer chromatography (1985)
    Springer
    Cancer chemotherapy and pharmacology 14 (1985), S. 139-145 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We compared doxorubicin and metabolite pharmacokinetic data obtained from thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) assay of plasma samples from six patients who had been treated with doxorubicin. Duplicate 1-ml samples were extracted with chloroform: isopropanol (1:1) and assayed using a sensitive HPLC system incorporating a dual pump gradient with tetrahydrofuran as the mobile phase and fluorescence detection. Duplicate 1-ml samples from the same specimens were assayed using a modification of a previously described TLC assay. Areas under the curve for doxorubicin by HPLC (3.36±2.30 μM · h) and TLC (4.16±2.50 μM · h) were not significantly different (P=0.5). Terminal half-life of doxorubicin by HPLC (28.0±6.98 h) and TLC (23.2±7.8) (P=0.29) and the calculated total-body clearances by HPLC (0.55±0.29 l/min) and TLC (0.45±0.23) (P=0.55) were not significantly different. Areas under the curve for doxorubicinol by HPLC (2.75±1.4 μM · h) and TLC (2.53±7.1 μM · h) (P=0.73) showed no significant differences. HPLC detected a mixed 7-deoxydoxorubicinol aglycone-doxorubicin aglycone peak, 7-deoxydoxorubicin aglycone, and two nonpolar, unidentified metabolites. TLC detected the following aglycone metabolites: doxorubicin aglycone, doxorubicinol aglycone, 7-deoxydoxorubicinol aglycone, an unidentified polar metabolite, and several unidentified nonpolar metabolites. From these data we conclude that HPLC and TLC detect concentrations of doxorubicin and doxorubicinol from human plasma equally well to concentrations of 7.0 nM (4 pmol injected doxorubicin). Aglycones do circulate in human plasma at concentrations above the detection limits of both assays. Doxorubicinol aglycone, which is detected by TLC but not by HPLC, may be formed from artifactual breakdown of doxorubicinol during TLC development. Unidentified nonpolar compounds seen on HPLC and TLC may represent further doxorubicin metabolism than previously described.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00434353
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