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1.
Barry J. Cusack Stephan P. Young Joni Driskell Richard D. Olson 《Cancer chemotherapy and pharmacology》1993,32(1):53-58
Cumulative dose-related, chronic cardiotoxicity is a serious clinical complication of anthracycline therapy. Clinical and animal studies have demonstrated that continuous infusion, compared to bolus injection of doxorubicin, decreases the risk of cardiotoxicity. Continuous infusion of doxorubicin may result in decreased cardiac tissue concentrations of anthracyclines, including the primary metabolite doxorubicinol, which may also be an important contributor to cardiotoxicity. In this study, doxorubicin and doxorubicinol plasma pharmacokinetics and tissue concentrations were compared in New Zealand white rabbits following intravenous administration of doxorubicin (5 mg·kg–1) by bolus and continuous infusion. Blood samples were obtained over a 72-h period after doxorubicin administration to determine plasma doxorubicin and doxorubicinol concentrations. Rabbits were killed 7 days after the completion of doxorubicin administration and tissue concentrations of doxorubicin and doxorubicinol in heart, kidney, liver, and skeletal muscle were measured. In further experiments, rabbits were killed 1 h after bolus injection of doxorubicin and at the completion of a 24-h doxorubicin infusion (anticipated times of maximum heart anthracycline concentrations) to compare cardiac concentrations of doxorubicin and doxorubicinol following both methods of administration. Peak plasma concentrations of doxorubicin (1739±265 vs 100±10 ng·ml–1) and doxorubicinol (78±3 vs 16±3 ng·ml–1) were significantly higher following bolus than infusion dosing. In addition, elimination half-life of doxorubicinol was increased following infusion. However, other plasma pharmacokinetic parameters for doxorubicin and doxorubicinol, including AUC, were similar following both methods of doxorubicin administration. Peak left ventricular tissue concentrations of doxorubicin (16.92±0.9 vs 3.59±0.72 g·g–1 tissue;P<0.001) and doxorubicinol (0.24±0.02 vs 0.09±0.01 g·g–1 tissue;P<0.01) following bolus injection of doxorubicin were significantly higher than those following infusion administration. Tissue concentrations of parent drug and metabolite in bolus and infusion groups were similar 7 days after dosing. The results suggest that cardioprotection following doxorubicin infusion may be related to attenuation of the peak plasma or cardiac concentrations of doxorubicin and/or doxorubicinol. 相似文献
2.
L. K. Webster E. J. Cosson K. H. Stokes M. J. Millward 《British journal of cancer》1996,73(4):522-524
The effect of the paclitaxel vehicle Cremophor on the pharmacokinetics of doxorubicin and doxorubicinol was studied in two groups of mice given intravenously either 2.5 ml kg-1 Cremophor or saline followed 5 min later by 10 mg kg-1 doxorubicin. In each group three mice were sacrificed at ten time points and doxorubicin and doxorubicinol were measured in plasma by high-performance liquid chromatography (HPLC). With Cremophor present, doxorubicin AUC increased from 1420+/-440 to 2770+/-660 ng h ml(-1) (P<0.05) and doxorubicinol AUC increased from 130+/-76 to 320+/-88 ng h ml(-1) (p<0.05). Neither the terminal elimination half-lives nor the doxorubicinol-doxorubicin AUC ratio changed in the presence of Cremophor, suggesting a lack of a direct effect on drug metabolism. The possibility exists the Cremophor may change the pharmacokinetics of both paclitaxel and other drugs given concurrently. 相似文献
3.
Barry J. Cusack Stephan P. Young Vicki L. Loseke Michelle R. Hurty Loring Beals Richard D. Olson 《Cancer chemotherapy and pharmacology》1992,30(2):145-148
Summary Malnutrition involving protein deficiency, which commonly occurs in cancer patients receiving anthracycline treatment, is considered to be a risk factor for the development of cardiotoxicity. Protein deficiency has been shown to impair the metabolism of drugs such as theophylline and acetaminophen. If protein deficiency also impairs anthracycline metabolism, it could explain at least in part the enchanced anthracycline toxicity associated with malnutrition. We tested this idea by determining the effect of a low- protein, isocaloric diet on doxorubicin pharmacokinetics in rabbits. The animals were randomized into two groups for 8–12 weeks. Rabbits in group 1 received a low-protein (5%), isocaloric diet, whereas those in group 2 received a normal-protein (15%) diet. Both groups (group 1,n=15; group 2,n=14) were given 5 mg/kg doxorubicin by i.v. bolus. After doxorubicin injection, blood samples were obtained over the next 52 h for the measurement of doxorubicin and doxorubicinol plasma concentrations by high-performance liquid chromatography (HPLC) with fluorometric detection. The low-protein diet significantly decreased doxorubicin clearance (48±3 vs 59±4 ml min–1 kg–1;P<0.05), prolonged the terminal climination half-life (28±2 vs 22±2 h;P<0.05), and increased the area under the plasma concentration/time curve extrapolated to infinity (1722±122 vs 1405±71 ng h ml–1;P<0.05) as compared with the values determined for rabbits fed the standard rabbit chow (15% protein). The volume of distribution for doxorubicin was not altered by the low-protein diet. In addition, in rabbits fed the the low-portein diet, the terminal elimination half-life of the alcohol metabolite, doxorubicinol was prolonged (52±5 vs 40±2 h;P<0.05). Thus, a low-protein diet causes a reduction in the ability of rabbits to eliminate doxorubicin and possibly its alcohol metabolite doxorubicinol. If a similar alteration in anthracycline pharmacokinetics occurs in malnourished cancer patients, this phenomenon may contribute to their increased risk of developing cardiotoxicity associated with anthracycline therapy.Supported by the Department of Veterans Affairs and the American Heart Foundation 相似文献
4.
Tissue distribution of doxorubicin and doxorubicinol in rats receiving multiple doses of doxorubicin 总被引:4,自引:0,他引:4
John H. Peters G. Ross Gordon David Kashiwase Edward M. Acton 《Cancer chemotherapy and pharmacology》1981,7(1):65-69
Summary Plasma and tissue levels of doxorubicin (DXR) and doxorubicinol (DXR-OL) were measured fluorometrically after high-pressure liquid chromatography at 1, 3, and 24 h following one, nine, and 24 doses of 1.0 mg DXR/kg or one and eight doses of 4.0 mg DXR/kg, IP, to rats. Comparison of plasma levels of DXR found following single and multiple doses suggests significant build-up of DXR at 1 h with successive doses, but not at 3 h. Liver exhibited substantially higher levels of DXR (on a per gram of protein basis) than did plasma, and multiple doses did not produce higher levels than did a single dose. In contrast, the heart accumulated DXR slowly, attaining levels after multiple dosing in excess of those found in the liver. Skeletal muscle exhibited dose-related levels similar to those for heart but the absolute levels of DXR in muscle were only about one-tenth of those observed in heart. DXR-OL was at very low levels of 4% of the DXR levels in the tissues; it was, however, a major circulatory metabolite, attaining levels in the plasma as high as 85% of the concentration of DXR. 相似文献
5.
Grossman SA Olson J Batchelor T Peereboom D Lesser G Desideri S Ye X Hammour T Supko JG;New Approaches to Brain Tumor Therapy CNS Consortium 《Neuro-oncology》2008,10(2):190-198
Cyclooxygenase-2 (COX-2) expression has been linked to the prognosis, angiogenesis, and radiation sensitivity of many malignancies. Celecoxib, a selective COX-2 inhibitor, is predominantly eliminated by hepatic metabolism. This study was conducted to determine the effects of hepatic enzyme-inducing antiseizure drugs (EIASDs) on the pharmacokinetics of celecoxib. The safety of celecoxib administered with radiation for glioblastoma and the effect of the combined treatment on survival were also evaluated. Patients were stratified based on concomitant use of EIASDs. Celecoxib (400) mg was administered orally twice a day until tumor progression or dose-limiting toxicity. Standard radiation was administered without adjuvant chemotherapy. Sampling was performed to define the plasma concentration/time profile for the initial dose of celecoxib and steady-state trough concentrations. Thirty-five patients (22 +EIASD, 13 -EIASD) were enrolled. There were no significant differences in age, performance status, extent of surgery, or Mini Mental State Exam scores between the two cohorts. The treatment was well tolerated. All patients in the +EIASD arm were taking phenytoin. There were no significant differences in any celecoxib pharmacokinetic parameters between 15 +EIASD and 12 -EIASD patients. With 31 of 35 patients deceased, estimated median survival time for all patients was 12 months (+EIASD, 11.5 months; - EIASD, 16 months; p = 0.11). The pharmacokinetics of celecoxib is not significantly affected by the concomitant administration of phenytoin. Celecoxib administered during and after radiation is well tolerated. The potential difference in survival between the +EIASD and -EIASD groups deserves further evaluation. 相似文献
6.
P Workman 《British journal of cancer》1979,40(3):335-353
Concentrations of the hypoxic cell radiosensitizer misonidazole (MIS) and its O-demethylated metabolite Ro 05-9963 were determined in plasma (or blood), brain and tumour after injection of 1 g/kg MIS i.p. to control mice or mice pretreated with 4-6 daily injections of phenobarbitone or phenytoin. Analysis was by high-performance liquid chromatography (HPLC). Phenobarbitone and phenytoin did not alter the peak MIS concentration in plasma, brain or tumor. However, the apparent elimination half-life (t 1/2) for MIS was reduced by 20-67%, and the area under the curve (AUC) was decreased by 23-49% in plasma, brain and tumour. The decrease in MIS t 1/2 was associated with an initially increased Ro 05-9963 metabolite concentration. However, the AUC for total 2-nitromidazole (MIS + Ro 05-9963) in plasma, tumour and brain was reduced by 20-50%. Urinary excretion of MIS and its metabolites accounted for 15-42% of the injected dose, and was unaltered by pretreatment with phenobarbitone or phenytoin. Tumour/plasm and brain/plasma concentration ratios for MIS, and tumour/plasma ratios for Ro 05-9963 were very similar, but the brain/tumour ratios for Ro 05-9963 were considerably lower. Tissue/plasma ratios were unaltered by pretreatment with phenobarbitone or phenytoin. The acute LD50 for MIS was increased from 1.54 to 1.90 g/kg after phenobarbitone pretreatment and 1.78 g/kg after phenytoin pretreatment. In addition, pretreatment with either compound shortened the duration of the MIS-induced decrease in body temperature. These data suggest that pretreatment with microsomal-enzyme-inducing agents may reduce the toxicity of MIS without affecting the radiosensitization. The significance of these findings for the mechanism of MIS toxicity is also discussed. 相似文献
7.
《International journal of hyperthermia》2013,29(4):545-559
Six cycles of the maximum tolerable intravenous doses of lonidamine (400 mg/m2) and doxorubicin (30 mg/m2) were administered to three normothermic dogs and three dogs undergoing whole-body hyperthermia (WBH) (42°C × 90 min), at 3-week intervals. Lonidamine pharmacokinetics was unaltered by WBH. WBH increased doxorubicin clearance 1·6-fold, however this trend was not statistically significant. WBH resulted in a 2·4-fold increase in the volume of distribution (Vdss) of doxorubicin relative to dogs treated under euthermic conditions (p < 0·001). This finding suggests tissue extraction of doxorubicin was increased by WBH. The specific tissues in which this occurred is unknown, but myelosuppression and cardiotoxicity were only minimally increased. Therefore, doxorubicin uptake in critical normal tissues was probably unaffected. The biochemical and haematologic toxicities observed 6 h and 1 week after each treatment did not appear to differ in character or severity from that reported in dogs receiving lonidamine ± WBH or doxorubicin ± WBH. These results suggest WBH did not decrease the maximum tolerable dose of doxorubicin when given with lonidamine, and that the antitumour activity of this combination should be assessed. 相似文献
8.
R A Newman D Dogramatzis J A Benvenuto M Trevino L C Stephens J Wondergem R Strebel H Baba J M Bull 《International journal of hyperthermia》1992,8(1):79-85
The effect of whole-body hyperthermia (41.5 degrees C, 2 h) on doxorubicin (DOX) tissue distribution and plasma pharmacokinetics was examined in rats bearing a subcutaneous fibrosarcoma. Tumour response to the hyperthermia regimen alone was minimal, but the combination of heat with DOX (5.0 mg/kg, i.v.) enhanced tumour growth delay. The combined therapy, however, showed increased toxicity to normal tissue (especially renal and cardiac). Although DOX levels in spleen tissue were higher in rats exposed to hyperthermia than in control normothermic rats, both groups had comparable levels of drug in tumour, heart, kidney, and small intestine tissue at all time-points examined. Compared with normothermic animals, hyperthermia-treated rats showed decreased DOX in the mean area under the concentration-time curve (AUC) and decreased plasma DOX t1/2 but increased plasma drug clearance. These heat-mediated alterations in DOX pharmacokinetic parameters, however, do not account for the significant increases in thermochemotherapy-mediated cytotoxicities observed in tumour, and in normal renal and cardiac tissues. 相似文献
9.
Pharmacokinetics of doxorubicin and its metabolite doxorubicinol in rabbits with induced acid and alkaline urine 总被引:1,自引:0,他引:1
Peter B. Johansen Svend E. Jensen Søren N. Rasmussen Mads Dalmark 《Cancer chemotherapy and pharmacology》1984,13(1):5-8
Summary The pharmacokinetics of doxorubicin in rabbits preloaded either with ammonium chloride or sodium hydrogencarbonate have been investigated following single IV administration of 5 mg/kg.Plasma samples and urine collections were obtained over 3 h following administratio, and were assayed in duplicate for doxorubicin and its main metabolite doxorubicinol by reversed-phase high-pressure liquid chromatography.The plasma concentration of doxorubicin was fitted to an open two-compartment model.The areas under the plasma concentration-time curves (AUC) of doxorubicin in rabbits with alkaline urine were approximately half the areas in rabbits with acid urine. A pharmacokinetic analysis indicated an increase in the central volume of distribution, which is interpreted as an increase in tissue permeability in the alkaline state, due to the acid-base properties of the doxorubicin molecule.The renal excretion of doxorubicin and doxorubicinol was quantitatively similar in the two groups of rabbits. The total renal excretion of anthracyclines during the experiment was calculated to approximately 6% of the administered dose. The clearances of doxorubicin were initially three times higher than inulin clearance, but approximated this value at the end of the experiment.The renal handling of doxorubicin in the rabbits is explained by glomerular filtration followed by tubular secretion and finally by a reabsorption mechanism with limited capacity. 相似文献
10.
Comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes 总被引:3,自引:0,他引:3
The comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes was evaluated in rats at a dose of 6 mg/kg i.v. Doxorubicin was entrapped in cardiolipin liposomes by using 11.2 mumol of drug, 5.6 mumol of cardiolipin, 28.5 mumol of phosphatidylcholine, 19.5 mumol of cholesterol, and 11.1 mumol of stearylamine. The peak plasma concentration with free doxorubicin at 5 min was 1.7 micrograms/ml which was reduced to 0.3 micrograms/ml by 1 h. With cardiolipin liposomes, the peak plasma concentration of doxorubicin achieved at 5 min was 20.9 micrograms/ml. The plasma levels of doxorubicin decreased gradually and by 1 h the drug concentration in plasma was 10 micrograms/ml. The plasma levels of free doxorubicin and doxorubicin entrapped in liposomes were fitted to a 3-compartment computer model. The terminal half-life with free doxorubicin in plasma was 17.3 h whereas it was 69.3 h with drug entrapped in liposomes. The area under the plasma concentration curve with liposomal doxorubicin was 81.4 micrograms X h X ml-1 compared to 1.95 micrograms X h X ml-1 observed with free doxorubicin. The steady state volume of distribution with free doxorubicin was about 23-fold higher than liposomal doxorubicin. The terminal half-life with free doxorubicin in cardiac tissue was 17.9 h compared to 12.6 h with drug encapsulated in liposomes. The terminal half-lives in liver and spleen following administration of liposomal doxorubicin were 15- and 2.3-fold higher, respectively, compared to free drug; furthermore, the concentration X time values of liposomal doxorubicin in liver were 26-fold higher and in spleen 6-fold higher than the free drug. Free doxorubicin and doxorubicin entrapped in liposomes demonstrated 17 and 20% excretion in bile of the injected dose, respectively, in rats. The present studies demonstrate that liposomal encapsulation of doxorubicin significantly alters its pharmacokinetics in plasma and tissues compared to free drug. 相似文献
11.
Effect of tamoxifen pretreatment on the pharmacokinetics, metabolism and cardiotoxicity of doxorubicin in female rats 总被引:2,自引:0,他引:2
The purpose of this study was to examine the effect of tamoxifen pretreatment on the metabolism and pharmacokinetics of doxorubicin.
We tested the hypothesis that the pretreatment would counteract the side effects of doxorubicin and modify the disposition
of the drug. The concentration-time profiles of doxorubicin in plasma and blood cells were determined in conjunction with
the cumulative amount of renal and hepatobiliary elimination of unchanged drug and metabolites following a 10-day tamoxifen
pretreatment at a dose of 1 mg/kg per day. Furthermore, under the same experimental protocol the serum concentration-time
profile of endothelin was determined as a biomarker of toxicity. Methods: Female Sprague Dawley rats (225–275 g), pretreated orally for 10 days with corn oil or tamoxifen in corn oil (1 mg/kg per
day), received 14C-doxorubicin (specific activity 0.4 μCi/mg, 10 mg/kg) intravenously. Plasma, blood cells, bile and urine were collected periodically
and analyzed for doxorubicin and its metabolites. Four other groups of animals received the same pretreatment and non-labeled
doxorubicin. Their serum samples were analyzed for endothelin. Two additional groups were also used to examine the effect
of tamoxifen on the in vitro metabolism of doxorubicin by the cytosolic enzyme aldo-keto reductase. Results: Tamoxifen pretreatment reduced the total protein of the cytosolic fraction by 50% and reduced the formation of doxorubicinol
both in vitro and in vivo. The pretreatment resulted in a notable increase in the area under plasma and blood cells concentration-time
curves of doxorubicin and a significant reduction in mean residence time, apparent volume of distribution and serum endothelin
levels. Conclusions: We attributed the increase in the area under the curves of plasma and blood cells following tamoxifen pretreatment to a
reduction in the uptake of doxorubicin by peripheral tissues. This conclusion was consistent with the reduction in the volume
of distribution of plasma, mean residence time and higher availability of the parent compound for excretion. An interesting
observation was that the increase in concentration of doxorubicin in plasma was not concomitant with an increase in concentration
of doxorubicinol. The levels of this toxic metabolite and its corresponding biliary rate constant were reduced by approximately
50%. The results demonstrate that tamoxifen, in addition to being a modulator of P-glycoprotein and counteracting the effects
of doxorubicin at the cellular level, also alters the metabolic profile of doxorubicin either by inhibiting the formation
of the toxic metabolite doxorubicinol or by reducing the enzyme responsible for the biotransformation. The change in metabolism
may well be a contributing factor to reduction of serum endothelin levels.
Received: 2 September 1999 / Accepted: 14 April 2000 相似文献
12.
Franca Formelli Loredana Cleris Roberto Carsana 《Cancer chemotherapy and pharmacology》1988,21(4):329-336
Summary The effect of the combined administration of verapamil (i.p. twice daily) and doxorubicin (i.v once weekly) was tested in mice bearing the following: (a) a tumor with induced resistance to doxorubicin (B16VDXR melanoma line); (b) a tumor inherently resistant (MXT mammary carcinoma); and (c) four solid tumors sensitive to doxorubicin (B16 melanoma, B16V melanoma line, M5076 reticulum cell sarcoma, and Lewis lung carcinoma). Verapamil, given according to this treatment schedule, reached peak plasma concentrations of 3 M. Such treatment did not enhance doxorubicin activity on either inherently or induced resistant tumors, whereas it significantly enhanced doxorubicin growth inhibition in all the sensitive tumors except the Lewis lung carcinoma. Doxorubicin pharmacokinetics after administration of the drug alone and in combination with verapamil was analyzed after the first and repeated treatments in animals bearing B16 melanoma or its resistant subline B16VDXR. The resistance of the B16VDXR line was associated with the ability of the tumor to retain less doxorubicin (AUC=83 g h/g) than the sensitive tumor B16 (AUC=204 g h/g) in spite of similar initial levels. The potentiating effect of doxorubicin activity by, verapamil in B16 melanoma was not associated with increased doxorubicin levels or retention in the tumor, nor were differences in doxorubicin levels or retention found in the B16VDXR line. The combined treatment did not modify doxorubicin pharmacokinetics in plasma, heart, or spleen. These studies suggest that verapamil in vivo is ineffective in potentiating doxorubicin activity in tumors against which doxorubicin is inactive, that sensitive tumors are heterogeneous in their sensitivity to modulation by verapamil, and that this effect is not associated with modification of doxorubicin pharmacokinetics.This work was supported by grant no. 84.00855.44 of the Finalized Project Oncologia from the Consiglio Nazionale delle Ricerche, Rome 相似文献
13.
J van Asperen O van Tellingen F Tijssen A H Schinkel J H Beijnen 《British journal of cancer》1999,79(1):108-113
To gain more insight into the pharmacological role of endogenous P-glycoprotein in the metabolism of the widely used substrate drug doxorubicin, we have studied the plasma pharmacokinetics, tissue distribution and excretion of this compound in mdr1a(-/-) and wild-type mice. Doxorubicin was administered as an i.v. bolus injection at a dose level of 5 mg kg(-1). Drug and metabolite concentrations were determined in plasma, tissues, urine and faeces by high-performance liquid chromatography. In comparison with wild-type mice, the terminal half-life and the area under the plasma concentration-time curve of doxorubicin in mdr1a(-/-) mice were 1.6- and 1.2-fold higher respectively. The retention of both doxorubicin and its metabolite doxorubicinol in the hearts of mdr1a(-/-) mice was substantially prolonged. In addition, a significantly increased drug accumulation was observed in the brain and the liver of mdr1a(-/-) mice. The relative accumulation in most other tissues was not or only slightly increased. The differences in cumulative faecal and urinary excretion of doxorubicin and metabolites between both types of mice were small. These experiments demonstrate that the absence of mdr1a P-glycoprotein only slightly alters the plasma pharmacokinetics of doxorubicin. Furthermore, the substantially prolonged presence of both doxorubicin and doxorubicinol in cardiac tissue of mdr1a(-/-) mice suggests that a blockade of endogenous P-glycoprotein in patients, for example by a reversal agent, may enhance the risk of cardiotoxicity upon administration of doxorubicin. 相似文献
14.
John R. Baldwin Barbara A. Phillips Stephen K. Overmyer Naomi Z. Hatfield Prem K. Narang 《Cancer chemotherapy and pharmacology》1992,30(6):433-438
Summary The influence of dexrazoxane on doxorubicin pharmacokinetics was investigated in four dogs using the two treatment sequences of saline/doxorubicin or dexrazoxane/doxorubicin. Intravenous doses of 1.5 mg/kg doxorubicin and 30 mg/kg (the 20-fold multiple) dexrazoxane were given separately, with doxorubicin being injected within 1 min of the dexrazoxane dose. Both doxorubicin and its 13-dihydro metabolite doxorubicinol were quantified in plasma and urine using a validated high-performance liquid chromatographic (HPLC) fluorescence assay. The doxorubicin plasma concentration versus time data were adequately fit by a three-compartment model. The mean half-lives calculated for the fast and slow distributive and terminal elimination phases in the saline/doxorubicin group were 3.0±0.5 and 32.2±12.8 min and 30.0±4.0 h, respectively. The model-predicted plasma concentrations were virtually identical for the saline and dexrazoxane treatment groups. Analysis of variance of the area under the plasma concentration-time curve (AUC0–), terminal elimination rate (Z), systemic clearance (CL
s), and renal clearance (CL
r) for the parent drug showed no statistically significant difference (P<0.05) between the two treatments. Furthermore, the doxorubicinol plasma AUC0– value and the doxorubicinol-to-doxorubicin AUC0– ratio showed no significant difference, demonstrating that dexrazoxane had no effect on the metabolic capacity for formation of the 13-dihydro metabolite. The total urinary excretion measured as parent drug plus doxorubicinol and the metabolite-to-parent ratio in urine were also unaffected by the presence of dexrazoxane. The myelosuppressive effects of doxorubicin as determined by WBC monitoring revealed no apparent difference between the two treatments. In conclusion, these results show that drug exposure was similar for the two treatment arms. No kinetic interaction with dexrazoxane suggests that its coadministration is unlikely to modify the safety and/or efficacy of doxorubicin. 相似文献
15.
N. Lindsay Harris Dean E. Brenner Lowell B. Anthony Jerry C. Collins Susan Halter Kenneth R. Hande 《Cancer chemotherapy and pharmacology》1988,21(4):323-328
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 M·h/ml vs 4.49±2.35 M·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.Grant support: Glaxo Inc., Veterans Administration, NIH BRSG RR-05424, NIH Grant RR-00095, Clinical Research Center. American Cancer Society Institutional Grant IN25V 相似文献
16.
Carlo M. Camaggi Raffaella Comparsi Elena Strocchi Fabio Testoni Bruna Angelelli Franco Pannuti 《Cancer chemotherapy and pharmacology》1988,21(3):221-228
Summary The pharmacokinetics and metabolism of doxorubicin (DX) and epirubicin (epiDX) were investigated in eight cancer patients who received 60 mg/m2 of both drugs independently by intravenous (i.v.) bolus at 3-week intervals according to a balanced cross-over design. Unchanged DX and epiDX plasma levels followed a triexponential decay. Half-lives (t/2) of the three decay phases were longer for DX (t/2: 4.8 vs. 3 min; t/2 2.57 h vs. 1.09 h; t/2 48.4 vs. 31.2 h). According to a model-independent analysis, the different plasma disposition kinetics of the two compounds appears to be related to a higher plasma clearance (PlCl) and to a lower mean residence time (MRT) of epiDX (PlCl: 75.0 l/h, range: 35.6–133.4 l/h; MRT: 31.6 h, range: 7.0–41.5 h;) compared to DX (PlCl: 56.8 l/h, range: 24.4–119.5; MRT: 45.6 h, range: 26.0–83.1 h). No statistically significant differences could be detected for the volume of distribution at steady state (Vss) (epiDX, 31.8 l/kg; DX, 33.3 l/kg). Metabolites common to both compounds were detected in plasma: the 13-dihydro derivatives doxorubicinol (DXol) and epirubicinol (epiDXol), together with monor amounts of four aglycones (7-deoxy adriamycinone, adriamycinone, 7-deoxy 13-dihydro adriamycinone, and 13-dihydro adriamycinone). Following epiDX administration, two additional major metabolites were detected: the glucuronic acid conjugates of epiDX (4-O--d-glucuronyl-4-epiDX) and epiDXol (4-O--d-glucuronyl 13-dihydro-4-epiDX). This additional detoxication route appears to account for the more efficient and faster elimination of epiDX than of DX. In the urine collected in the 6 days after treatment, 12.2% of the DX and 11.9% of the epiDX dose was excreted as unchanged drug and fluorescent metabolites. A comparable renal clearance was calculated for DX (4.7 l/h, range 1.4–7.0 l/h) and epiDX (4.4 l/h, range 1.7–7.0 l/h). One patient with hepatic metastates and abnormal bilirubin serum level had percutaneous biliary drainage because of extrahepatic obstruction. The elimination of both drugs was significantly impaired in this patient; nevertheless, elimination of epiDX was still more efficient and faster than that of DX (PlCl: 35.6 vs. 24.4 l/h; MRT: 39.0 vs. 83.1 h; t/2: 47 vs. 74 h). This patient's biliary excretion accounted for 35.4% of the epiDX dose and 18.2% of the DX dose.Supported in part by contract CNR, No. 85.02282.44 (Progetto Finalizzato Oncologia) 相似文献
17.
D E Brenner L B Anthony S Halter N L Harris J C Collins K R Hande 《Cancer research》1987,47(12):3259-3265
A model of hepatic dysfunction in vivo has been developed in rabbits to determine the effects of sublethal hepatocellular necrosis upon doxorubicin pharmacology. Eight New Zealand white rabbits were given 3 mg/kg doxorubicin i.v. Plasma doxorubicin and metabolite pharmacokinetics were determined and toxicity assessed by nadir complete blood counts. Hepatic function was assessed by the pulmonary excretion rate of 14CO2 from [14C]aminopyrine. Hepatocellular necrosis was produced by i.v. injection of 1.35 mg/kg of a 2% allyl alcohol solution. Doxorubicin administration and pharmacokinetics were repeated. Doxorubicin enhances the hepatotoxicity of allyl alcohol. Hepatocellular necrosis does not alter the plasma pharmacokinetics of doxorubicin but does increase the plasma exposure of doxorubicinol. Doxorubicin-induced myelosuppression is enhanced by allyl alcohol pretreatment. These data suggest that in circumstances of reduced hepatocellular volume or acute hepatocellular necrosis, a key plasma marker of doxorubicin-induced acute toxicity may be doxorubicinol. 相似文献
18.
19.
La-Beck NM Zamboni BA Gabizon A Schmeeda H Amantea M Gehrig PA Zamboni WC 《Cancer chemotherapy and pharmacology》2012,69(1):43-50
Purpose
There is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD. 相似文献20.
《European journal of cancer & clinical oncology》1987,23(3):303-309
The antineoplastic activity of the anthracyclin antibiotic doxorubicin (Adriamycin®) differs in its cytotoxic effectiveness against different types of human tumors. In the present study the effect of doxorubicin on the growth of two human lung carcinomas and one human mammary carcinoma transplanted into athymic mice was correlated with the pharmacokinetics of doxorubicin in the same tumors after intraperitoneal administration. Doxorubicin produced a greater inhibition of tumor growth in the lung carcinomas than in the mammary carcinoma. Furthermore, the pharmacokinetic characteristics of doxorubicin differed widely within the three human solid tumors. No apparent correlation was found to exist between the different tumor growth sensitivities to doxorubicin and the pharmacokinetic parameters of doxorubicin within the tumor tissue. It is suggested that the differences in the demontrated antitumor effectiveness of doxorubicin may be due to differences in the “intrinsic sensitivity” of the three human solid tumors. 相似文献