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1.
E. Gupta Xiaolin Wang Jacqueline Ramirez M. J. Ratain 《Cancer chemotherapy and pharmacology》1997,39(5):440-444
Purpose: Irinotecan (CPT-11) is hydrolyzed to its active metabolite SN-38 which is subsequently conjugated by uridine diphosphate
glucuronosyl transferase (UDP-GT) to the glucuronide (SN-38G). Both preclinical and clinical data indicate that conjugation
is a primary clearance mechanism for SN-38 with the plasma glucuronide levels being substantially higher than those of SN-38.
This investigation was designed to determine the possibility of modulation of glucuronidation of SN-38 and its effect on the
disposition of the parent drug and metabolites. Methods: Female Wistar rats were pretreated with 200 mg/kg valproic acid (VPA), an inhibitor of glucuronidation, 5 min prior to the
administration of 20 mg/kg irinotecan. The control rats were given 20 mg/kg irinotecan only. To study the effect of inducers
of UDP-GT activity, rats were pre- treated with phenobarbital (PB) before irinotecan administration. Results: Pretreatment with VPA caused a 99% inhibition in the formation of SN-38G leading to a 270% increase in the area under plasma
concentration-time curve (AUC) of SN-38 compared with the control rats. The irinotecan estimations were unchanged in the two
groups. PB pretreatment caused a 1.7-fold increase in the AUC of SN-38G and a concomitant 31% and 59% reduction in the AUCs
of SN-38 and irinotecan, respectively. Conclusions: The most plausible explanation for the alterations in SN-38G disposition is inhibition of SN-38 conjugation by VPA and induction
of the conjugation by PB.
Received: 5 February 1996 / Accepted: 30 July 1996 相似文献
2.
Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates 总被引:1,自引:0,他引:1
Susan M. Blaney Chris Takimoto Daryl J. Murry Nancy Kuttesch Cynthia McCully Diane E. Cole Karen Godwin Frank M. Balis 《Cancer chemotherapy and pharmacology》1998,41(6):464-468
Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan,
were studied in a nonhuman primate model to determine their CSF penetration. Methods: 9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms
of 9-AC, irinotecan, and the active metabolite of irinotecan, SN-38, were quantified by reverse-phase HPLC. Results: 9-AC lactone had a clearance (CL) of 2.1 ± 0.9 l/kg per h, a volume of distribution at steady state (Vdss) of 1.6 ± 0.7 l/kg and a half-life (t1/2) of 3.2 ± 0.8 h. The lactone form of 9-AC accounted for 26 ± 7% of the total drug in plasma. The CSF penetration of 9-AC
lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUCCSF: AUCP) was only 3.5 ± 2.1%. For irinotecan, the CL was 3.4 ± 0.4 l/kg per h, the Vdss was 7.1 ± 1.3 l/kg, and the t1/2 was 4.9 ± 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone
form of irinotecan accounted for 26 ± 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 ± 6%
of the total SN-38 in plasma. The AUCCSF: AUCP ratio for irinotecan lactone was 14 ± 3%. SN-38 lactone and carboxylate could not be measured (<1.0 nM ) in CSF. The AUCCSF: AUCP ratio for SN-38 lactone was estimated to be ≤ 8%. Conclusion: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan
which we previously found to have an AUCCSF: AUCP ratio of 32%.
Received: 15 July 1997 / Accepted: 8 October 1997 相似文献
3.
Makoto Inaba Yasuyuki Ohnishi Hajime Ishii Yoshikuni Tanioka Ysaushi Yoshida Kenichi Sudoh Hideo Hakusui Naomi Mizuno Kiyomi Ito Yuichi Sugiyama 《Cancer chemotherapy and pharmacology》1997,41(2):103-108
Purpose: To examine the pharmacokinetic relationships between humans and monkeys, we studied the disposition of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin
(CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), in rhesus monkeys. Methods: CPT-11 was administered to a total of six monkeys at doses of 3, 7, 15 and 25 mg/kg by intravenous infusion for 10 min and
plasma concentrations and pharmacokinetic parameters of CPT-11 determined. Results: Maximum plasma concentrations at 25 mg/kg reached around 10 000 ng/ml, and dropped to 500 ng/ml in 8 h. Plasma concentrations
of SN-38 remained between 2 and 10 ng/ml. Mean values of systemic clearance, mean residence time and distribution volume at
steady state, the major pharmacokinetic parameters for CPT-11, were 13.3 (ml/min per kg), 192 (min) and 2553 (ml/kg), respectively.
The initial plasma concentration ratio of lactone to total CPT-11, 76%, declined to about 20% within 75 min, and the final
ratio was about 40% at 8 h; the initial ratio of SN-38 was 72%, dropped to 34% within 70 min and finally recovered to 55%
at 8 h. Conclusion: Comparison with human data revealed that systemic clearances of CPT-11 and the maximum AUC of SN-38 were not as different
between humans and monkeys as between humans and mice, but the metabolic conversion of CPT-11 into SN-38 in monkeys was significantly
lower than in humans.
Received: 19 December 1996 / Accepted: 9 May 1997 相似文献
4.
Poujol S Bressolle F Duffour J Abderrahim AG Astre C Ychou M Pinguet F 《Cancer chemotherapy and pharmacology》2006,58(3):292-305
Purpose: Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic–pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites. Methods: Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m²; 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection. Results: The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m² and 211 l/m², respectively. The intrapatient variability (22–28%) was far lower than the interindividual variability (33–88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs. Conclusions: All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant. 相似文献
5.
Kiyoshi Takasuna Takehiro Hagiwara Masaaki Hirohashi Michiyuki Kato Mamoru Nomura Eiichi Nagai Tsuyoshi Yokoi Tetsuya Kamataki 《Cancer chemotherapy and pharmacology》1998,42(4):280-286
Purpose: SN-38, a metabolite of irinotecan hydrochloride (CPT-11), is considered to play a key role in the development of diarrhea
as well as in the antitumor activity of CPT-11. We have previously found that the inhibition of β-glucuronidase, which hydrolyzes
detoxified SN-38 (SN-38 glucuronide) to reform SN-38, in the lumen by eliminating the intestinal microflora with antibiotics,
markedly ameliorates the intestinal toxicity of CPT-11 in rats. In this study we compared the disposition of CPT-11 and its
metabolites in rats treated with and without antibiotics. Methods: Rats were given drinking water containing 1 mg/ml penicillin and 2 mg/ml streptomycin from 5 days before the administration
of CPT-11 (60 mg/kg i.v.) and throughout the experiment. CPT-11, SN-38 glucuronide and SN-38 concentrations in the blood,
intestinal tissues and intestinal luminal contents were determined by HPLC. Results: Antibiotics had little or no effect on the pharmacokinetics of CPT-11, SN-38 glucuronide or SN-38 in the blood, or in the
tissues or contents of the small intestine, which has less β-glucuronidase activity in its luminal contents. In contrast,
antibiotics markedly reduced the AUC1–24 h of SN-38 (by about 85%) in the large intestine tissue without changing that of CPT-11, and this was accompanied by a complete
inhibition of the deconjugation of SN-38 glucuronide in the luminal contents. Conclusions: These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by β-glucuronidase in the intestinal
microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the
β-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine.
Received: 8 August 1997 / Accepted: 16 January 1998 相似文献
6.
Keizo Sugimachi Yoshihiko Maehara Michio Ogawa Teruo Kakegawa Masao Tomita 《Cancer chemotherapy and pharmacology》1997,40(3):233-238
A retrospective analysis of postoperative chemotherapy had shown the continuous administration of UFT, an oral preparation
of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil at a molar ratio of 1:4, to be effective for poorly differentiated
gastric cancer. We therefore sought to determine prospectively the effective dose of postoperative chemotherapy with UFT for
patients with poorly differentiated gastric cancer following a curative resection. We determined the effect of the combined
intravenous administration of mitomycin C (MMC) and oral treatment with protein-bound polysaccharide Kreha (PSK), extracted
from the basidiomycete Coriolus versicolor, and UFT at a dose of either 8 mg/kg or 12 mg/kg daily for 1 year. A total of 224 patients with poorly differentiated stage
II–IV gastric cancer were entered into this study after undergoing a curative resection. No differences were observed between
the two treatment groups in terms of prognostic factors, the toxicity rate or the doses of the drugs prescribed, other than
UFT. The higher dose of UFT in maintenance therapy led to a decrease in the recurrence rate (P < 0.05), and increases in disease-free survival and cause-specific survival (P < 0.05). UFT at 12 mg/␣kg in postoperative chemotherapy was thus found- to improve the postoperative results with no increase
in toxicity for poorly differentiated gastric cancer, and is also cost-effective for outpatients.
Received: 8 February 1996 / Accepted: 27 November 1996 相似文献
7.
Modified irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onset diarrhea in rats 总被引:7,自引:0,他引:7
Kurita A Kado S Kaneda N Onoue M Hashimoto S Yokokura T 《Cancer chemotherapy and pharmacology》2000,46(3):211-220
Purpose: Clinically, diarrhea is the major dose-limiting toxicity of irinotecan hydrochloride (CPT-11). Using a rat model, we attempted
to decrease the incidence of delayed-onset diarrhea by modifying the administration schedule of CPT-11, and studied the pharmacokinetics
in this model in relation to the incidence of diarrhea. Methods: CPT-11 (total dose, 240 mg/kg) was administered intravenously (i.v.) to rats according to various schedules, and the incidence
of delayed-onset diarrhea was monitored. Results: Administration of CPT-11 at a dose of 60 mg/kg once daily for four consecutive days induced severe diarrhea, while at 30 mg/kg
twice daily at an interval of 9 h (daily dose 60 mg/kg) for four consecutive days alleviated the diarrheal symptoms, and at
30 or 40 mg/kg once daily for eight or six consecutive days, respectively, diarrhea was hardly induced. With the first schedule,
mucosal impairment of the cecal epithelium was observed, including wall thickening, edema, decrease in crypt number and size,
and formation of pseudomembrane-like substance, whereas these changes were less severe with the second schedule and were hardly
observed with the other two schedules. The areas under the plasma and cecal tissue concentration-time curves (AUCpla and AUCcec), the maximum plasma concentrations (Cmax) and the biliary excretions of CPT-11 and its metabolites, 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G)
in rats depended on the daily dose of CPT-11. Exceptionally, CPT-11 Cmax was significantly lower and SN-38 AUCcec was larger in the animals treated at 30 mg/kg twice daily than in those treated at 60 mg/kg once daily. Conclusion: These results suggested that the duration of exposure to both CPT-11 and SN-38 of the intestinal epithelium and CPT-11 plasma
Cmax are closely related to the incidence and severity of CPT-11-induced delayed-onset diarrhea in rats.
Received: 16 June 1999 / Accepted: 26 April 2000 相似文献
8.
M J de Jonge J Verweij P de Bruijn E Brouwer R H Mathijssen R J van Alphen M M de Boer-Dennert L Vernillet C Jacques A Sparreboom 《Journal of clinical oncology》2000,18(1):195-203
PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of irinotecan and cisplatin administered once every 3 weeks in a dose-escalating study in patients with solid tumors. PATIENTS AND METHODS: Fifty-two cancer patients were treated with irinotecan administered as a 90-minute infusion at doses ranging from 175 to 300 mg/m(2) followed by cisplatin administered as a 3-hour intravenous infusion at doses ranging from 60 to 80 mg/m(2). After reaching the maximum-tolerated dose, the sequence of drug administration was revised. For pharmacokinetic analysis, serial plasma samples were obtained on days 1 through 3 of the first cycle. Forty-five patients were assessable for irinotecan pharmacokinetics, and 46 were assessable for cisplatin pharmacokinetics. RESULTS: Irinotecan and cisplatin demonstrated linear pharmacokinetics comparable to that observed with single-agent administration, which suggests an absence of pharmacokinetic interaction. SN-38G constituted the major plasma metabolite of irinotecan, whereas 7-ethyl-10-[4-N-(1-piperidino)1-amino]-carbonyloxycamptothecine (NPC) was only a minor metabolite in plasma, possibly indicating a rapid conversion of NPC to SN-38. The terminal elimination phases of SN-38 and SN-38G were similar and relatively delayed when compared with the elimination of irinotecan. Maximal DNA adduct formation did not significantly differ from that observed with single-agent administration. The percentage decrease in WBC was significantly related to the areas under the plasma concentration-time curve (AUCs) of the lactone form of irinotecan (P =.0245) and SN-38 (P =. 0123). The severity of diarrhea was not significantly related to the AUCs of irinotecan and SN-38, nor to the systemic glucuronidation rate of SN-38. CONCLUSION: There was no apparent pharmacokinetic interaction between irinotecan and cisplatin in this study. Reversion of the administration sequence of the drugs did not seem to have any influence on the pharmacokinetics. The incidence and severity of delayed-type diarrhea was not related to any of the studied parameters. 相似文献
9.
Pharmacokinetics of irinotecan and its metabolites SN-38 and APC in children with recurrent solid tumors after protracted low-dose irinotecan. 总被引:3,自引:0,他引:3
M K Ma W C Zamboni K M Radomski W L Furman V M Santana P J Houghton S K Hanna A K Smith C F Stewart 《Clinical cancer research》2000,6(3):813-819
Irinotecan (IRN), a topoisomerase I interactive agent, has significant antitumor activity in early Phase I studies in children with recurrent solid tumors. However, the disposition of IRN and its metabolites, SN-38 and APC, in children has not been reported. Children with solid tumors refractory to conventional therapy received IRN by a 1-h i.v. infusion at either 20, 24, or 29 mg/m2 daily for 5 consecutive days for 2 weeks. Serial blood samples were collected after doses 1 and 10 of the first course. IRN, SN-38, and APC lactone concentrations were determined by an isocratic high-performance liquid chromatography assay. A linear four-compartment model was fit simultaneously to the IRN, SN-38, and APC plasma concentration versus time data. Systemic clearance rate for IRN was 58.7 +/- 18.8 liters/h/m2 (mean +/- SD). The mean +/- SD ng/ml x h single-day lactone SN-38 area under the concentration-time curve (AUC(0-->6) was 90.9 +/- 96.4, 103.7 +/- 62.4, and 95.3 +/- 63.9 at IRN doses of 20, 24, and 29 mg/m2, respectively. The relative extent of IRN conversion to SN-38 and metabolism to APC measured after dose 1 were 0.49 +/- 0.33 and 0.29 +/- 0.17 (mean +/- SD). No statistically significant intrapatient difference was noted for SN-38 area under the concentration-time curve. Large interpatient variability in IRN and metabolite disposition was observed. The relative extent of conversion and the SN-38 systemic exposure achieved with this protracted schedule of administration were much greater than reported in adults or children receiving larger intermittent doses. 相似文献
10.
Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy. 总被引:3,自引:0,他引:3
Kristine R Crews Clinton F Stewart Dana Jones-Wallace Stephen J Thompson Peter J Houghton Richard L Heideman Maryam Fouladi Daniel C Bowers Murali M Chintagumpala Amar Gajjar 《Clinical cancer research》2002,8(7):2202-2209
PURPOSE: The purpose of this study was to determine the effect of enzyme-inducing anticonvulsants (EIAs) on the disposition of irinotecan and metabolites in pediatric patients with high-grade glioma. EXPERIMENTAL DESIGN: Pediatric patients with newly diagnosed high-grade glioma were enrolled on this study between March 1999 and February 2001. During course 1, irinotecan was administered as a 60-min i.v. infusion at a dosage of 20 mg/m(2)/day for 5 days of 2 consecutive weeks. On days 1 and 12 of course 1, we collected serial plasma samples to measure the concentrations of the lactone and total forms of irinotecan and its metabolites SN-38 (7-ethyl-10-hydroxycamptothecin), SN-38 glucuronide (7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]camptothecin), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin. RESULTS: Thirty-one patients were enrolled. In patients receiving EIAs, the area under the concentration versus time curve (AUC) of irinotecan lactone and SN-38 lactone was significantly lower (P = 0.01 and P = 0.002, respectively), and the irinotecan lactone clearance was significantly higher (P = 0.0003), as compared with those in patients who received no EIAs. The glucuronidation ratio was higher (P = 0.0009), and the ratio of SN-38 AUC to irinotecan AUC was lower (P = 0.02) in patients who received EIAs. Two patients receiving EIAs tolerated increased irinotecan dosages of 30 and 40 mg/m(2)/day without toxicity. One patient receiving EIAs experienced grade 3 diarrhea when the dosage of irinotecan was increased to 60 mg/m(2)/day. CONCLUSIONS: EIAs increase the clearance of irinotecan and cause a decrease in systemic exposure to the active metabolite SN-38. Patients who are receiving irinotecan and who require anticonvulsants should be placed on non-EIA therapy, when possible. 相似文献
11.
Purpose: Nitrobenzylthioinosine (NBMPR), a potent inhibitor of nucleoside transport in many cell types, modulates the in vivo disposition
of several cytotoxic nucleoside analogs. In this study, a radioligand binding assay was developed for measurement of the NBMPR
content of plasma and erythrocytes. Methods: The assay was based on the competition between NBMPR and [3H]NBMPR for high-affinity sites on human erythrocyte membranes. With this assay, we followed in mice changes in the NBMPR
content of blood plasma and erythrocytes, following the intraperitoneal injection of the disodium salt of NBMPR 5′-monophosphate
(NBMPR-P), a prodrug form of NBMPR. Results: The radioligand binding assay was able to measure precisely as little as 2.5 pmol of NBMPR, allowing the direct determination
of NBMPR concentrations in plasma as low as 16 nM. As few as 8 × 103 molecules of NBMPR per cell could be determined in erythrocytes. The NBMPR content of plasma from mice injected with NBMPR-P
was maximal at about 20 min after injection and declined to <0.2% of the peak value by 10 h. Erythrocyte-associated NBMPR
was also maximal at 20 min, and declined to 11% of the peak value by 10 h after injection. Time courses for the disappearance
of NBMPR from plasma and erythrocytes were monoexponential and yielded half-life values of 0.39 h and 0.68 h, respectively,
an apparent volume of distribution of 0.61 l/kg, and a clearance of 1.1 l/h per kg. Conclusions: The radioligand binding assay is a sensitive and facile method for monitoring NBMPR concentrations in mammalian plasma and
tissue extracts.
Received: 20 August 1995 / Accepted: 17 December 1996 相似文献
12.
Federico Innocenti Romano Danesi Guido Bocci Stefano Fogli Antonello Di Paolo M. Del Tacca 《Cancer chemotherapy and pharmacology》1999,43(2):133-140
Purpose: To describe the metabolism of 6-mercaptopurine (6-MP) in erythrocytes and tissues of rats after repeated administration
of 6-MP at two dose levels and to provide evidence that in vivo modulation of 6-MP anabolism can be obtained by simultaneous
treatment with ribavirin or hydroxyurea, two inhibitors of enzymes involved in the bioactivation of 6-MP to the active 6-thioguanine
nucleotides (6-TGN). Methods: Rats were treated i.p. with 6-MP at 12.5 and 25 mg/kg daily for 12 days and erythrocyte, liver, and kidney levels of 6-mercaptopurine
nucleotides (6-MPN) and 6-TGN were investigated during the accumulation phase and for 50 days after the end of treatment.
In combination studies, ribavirin at 75 and 100 mg/kg per day (for 6-MP, 25 and 12.5 mg/kg per day) or hydroxyurea at 200
mg/kg per day were given i.p. for 12 days. The measurements of thionucleotide levels in rat samples were performed by high-pressure
liquid chromatography (HPLC). Results: The maximal concentration (Cmax) and the area under the concentration versus time curve (AUC) of 6-MPN and 6-TGN in erythrocytes and tissues increased significantly
after the administration of 6-MP at 25 mg/kg per day as compared with 12.5 mg/kg per day. In particular, the Cmax and AUC of 6-TGN in erythrocytes of rats treated with 6-MP at 25 mg/kg per day were approximately 5-fold higher than the
6-TGN values observed following treatment at 12.5 mg/kg per day. Moreover, 6-TGN levels in erythrocytes were significantly
higher than those of 6-MPN (910.9 ± 53.1 and 286.8 ± 23.4 pmol/8 × 108 cells for 6-TGN and 6-MPN, respectively, P < 0.05) after treatment with 6-MP at 25 mg/kg per day. The administration of ribavirin, an inhibitor of inosine monophosphate
dehydrogenase, in association with 6-MP increased the amount of 6-MPN detected in erythrocytes and tissues while reducing
6-TGN levels in samples. The production and accumulation of 6-MPN and 6-TGN were increased in erythrocytes and tissues by
hydroxyurea, an inhibitor of ribonucleotide reductase. Finally, a significant correlation between thionucleotide concentrations
and erythrocyte counts was observed. Conclusion: The overall results demonstrate that 6-MP is actively metabolized in rats and that its biotransformation can be modulated
by agents acting on enzymes of the purine metabolism, resulting in significant changes in erythrocyte and tissue levels of
6-MPN and 6-TGN. These findings provide evidence that the rat is a suitable model for investigation of the metabolism of 6-MP
and its possible pharmacologic modulation.
Received: 17 December 1997 / Accepted: 29 June 1998 相似文献
13.
Younis IR Malone S Friedman HS Schaaf LJ Petros WP 《Cancer chemotherapy and pharmacology》2009,63(3):517-524
Background Enterohepatic recirculation of irinotecan and one of its metabolites, SN-38, has been observed in pharmacokinetic data sets
from previous studies. A mathematical model that can incorporate this phenomenon was developed to describe the pharmacokinetics
of irinotecan and its metabolites.
Patients and methods A total of 32 patients with recurrent malignant glioma were treated with weekly intravenous administration of irinotecan at
a dose of 125 mg/m2. Plasma concentrations of irinotecan and its three major metabolites were determined. Pharmacokinetic models were developed
and tested for simultaneous fit of parent drug and metabolites, including a recirculation component.
Results Rebound in the plasma concentration suggestive of enterohepatic recirculation at approximately 0.5–1 h post-infusion was observed
in most irinotecan plasma concentration profiles, and in some plasma profiles of the SN-38 metabolite. A multi-compartment
model containing a recirculation chain was developed to describe this process. The recirculation model was optimal in 22 of
the 32 patients compared to the traditional model without the recirculation component.
Conclusion A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears
to improve characterization of this drug’s disposition in patients with glioma. 相似文献
14.
Our previous studies have suggested that the ineffectiveness of intravesical mitomycin C or doxorubicin therapy against muscle-invading
bladder cancer is in part because of the inability of these drugs to penetrate the urothelium (the urothelial drug concentration
is <5% of the concentration in urine). The goal of the present study was to identify agents that are efficiently absorbed
across the urothelium. To evaluate the potential use of taxol in intravesical therapy for bladder cancer, we examined the
bladder tissue and systemic plasma pharmacokinetics of intravesical taxol in dogs. Animals (∼8 kg body weight) were given
an instillation of taxol at 500 μg in 20 ml water. At 120 min postinstillation, the bladder was emptied and excised, and about
85% of the dose was recovered in the urine. The taxol concentration in the urothelium was about 50% of the concentration in
the urine, the concentrations then declined logarithmically in the underlying capillary-perfused tissues. The average tissue
concentration (∼2 μg/g) was two to three times the reported plasma concentration of 0.75 μg/ml in patients following intravenous
infusion of the >100-fold higher dose of 250 mg/m2. The steady-state plasma concentration was <0.02% of the average tissue concentration, and was <0.05% of the maximally tolerated
plasma concentration in patients. The octanol:water partitioning coefficients of taxol, doxorubicin, and mitomycin were >99,
0.52, and 0.41, which parallels the rank order of the partitioning across urothelium, i.e. taxol (∼50%) >> doxorubicin ≈ mitomycin
C (∼3%). In summary, the partitioning of taxol across the urothelium was more favorable than the partitioning of mitomycin
C and doxorubicin, and the systemic concentration of taxol resulting from intravesical treatment was insignificant in spite
of the extensive absorption into the bladder. We conclude that intravesical delivery of taxol provides a significant bladder
tissue targeting advantage, and that taxol represents a viable candidate drug for intravesical bladder cancer therapy.
Received: 20 September 1996 / Accepted: 2 December 1996 相似文献
15.
Kathleen W. Mosure Arris J. Henderson Lewis J. Klunk J. O. Knipe 《Cancer chemotherapy and pharmacology》1997,40(3):251-258
Purpose: The chimeric BR96–doxorubicin (DOX) immunoconjugate, BMS 182248, has induced remissions and cures of human lung adenocarcinoma
(L2987) implanted in athymic mice. The purpose of this study was to evaluate the biodistribution of DOX after BMS 182248 administration
to tumor-bearing mice and to evaluate the ability of BMS 182248 to target DOX to tumors. Methods: For this evaluation, L2987-implanted mice were given BMS 182248 (5 mg DOX/kg; three doses 4 days apart) and the levels of
both conjugate-bound and free DOX in plasma, tumor, liver and heart were determined. Results: Conjugate-bound DOX comprised the majority of plasma DOX, with relatively low levels of free DOX present. From plasma, conjugate-bound
DOX distributed to the tissues examined with the order of concentration (per gram of tissue) being tumor > liver > heart.
Free DOX was also detected in liver and heart, but at concentrations lower than those present after an equivalent DOX dose
(5 mg/kg; three doses 4 days apart). The total exposure of heart to free DOX after BMS 182248 administration was about one-
quarter of that found after the administration of DOX alone. The elimination kinetics of both conjugate-bound and free DOX
from heart and liver after BMS 182248 administration paralleled those observed from plasma, indicating that equilibrium had
been attained between these nontumor tissues and plasma. The elimination kinetics of both entities from tumors, however, were
different from those from plasma, liver and heart. BMS 182248 produced sustained levels of both conjugate-bound and free DOX
which were present throughout the experiment. This suggested that, in contrast to normal tissues, tumor tissue retention of
BMS 182248 by antigen-promoted binding had occurred and that the kinetics of free DOX in the tumors were controlled by the
rate of release of DOX from tumor-associated BMS 182248. As a result of this retention, the tumor concentrations of free DOX
after BMS 182248 administration exceeded those produced by i.v. administration of DOX at the same dose, a finding consistent
with the greater antitumor activity of BMS 182248 relative to DOX. BMS 182248 also liberated DOX upon incubation with rat
liver lysosomes and was accumulated by L2987 cells in culture, with the subsequent intracellular release of DOX. Conclusions: BMS 182248 effectively delivered DOX to L2987 xenografts implanted in athymic mice and produced higher and more prolonged
tumor concentrations of free DOX than the administration of DOX alone. Following BMS 182248 administration, normal tissues
(liver and heart) were exposed to lower overall concentrations of free DOX than were produced by administration of an equivalent
DOX dose.
Received: 18 June 1996 / Accepted: 27 November 1996 相似文献
16.
R L Drengler J G Kuhn L J Schaaf G I Rodriguez M A Villalona-Calero L A Hammond J A Stephenson S Hodges M A Kraynak B A Staton G L Elfring P K Locker L L Miller D D Von Hoff M L Rothenberg 《Journal of clinical oncology》1999,17(2):685-696
PURPOSE: We conducted a phase I dose-escalation trial of orally administered irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: CPT-11 solution for intravenous (IV) use was mixed with CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starting dosages ranged from 20 to 100 mg/m2/d. RESULTS: Grade 4 delayed diarrhea was the DLT at the 80 mg/m2/d dosage in patients younger than 65 years of age and at the 66 mg/m2/d dosage in patients 65 or older. The other most clinically significant toxicity of oral CPT-11 was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38 total) + AUC(SN-38G total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal cancer and liver metastases who received oral CPT-11 at the 80 mg/m2/d dosage achieved a confirmed partial response. CONCLUSION: The MTD and recommended phase II dosage for oral CPT-11 is 66 mg/m2/d in patients younger than 65 years of age and 50 mg/m2/d in patients 65 or older, administered daily for 5 days every 3 weeks. The DLT of diarrhea is similar to that observed with IV administration of CPT-11. The biologic activity and favorable pharmacokinetic characteristics make oral administration of CPT-11 an attractive option for further clinical development. 相似文献
17.
Allegrini G Falcone A Fioravanti A Barletta MT Orlandi P Loupakis F Cerri E Masi G Di Paolo A Kerbel RS Danesi R Del Tacca M Bocci G 《British journal of cancer》2008,98(8):1312-1319
The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapy-refractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m(-2) day(-1) (n=7), 2.8 mg m(-2) day(-1) (n=5) and 4.2 mg m(-2) day(-1) (n=8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C(ss)) of SN-38 were between 1 and 3.3 ng ml(-1). From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4+/-30.1 and 130.4+/-9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m(-2) day(-1) dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities >grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations. 相似文献
18.
Denis J. Morgan John S. Hill K. Clarke S. S. Stylli Samantha J. Park Jonathan Cebon Russell L. Basser Andrew H. Kaye Howard Geldard Darryl W. Maher Michael D. Green 《Cancer chemotherapy and pharmacology》1997,40(3):202-208
The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline
drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment
with drug given i.v. at doses of 10–50 mg/m2 (total dose 16.8–107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 ± 1.68 l/min, the mean volume of
distribution at steady state was 1460 ± 749 l and mean elimination half-life was 10.8 ± 5.1 h. The area under the plasma concentration-time
curve (AUC) of MX2 was linearly related to the dose per kilogram and the dose per body surface area (r
2 = 0.43, P < 0.01 and r
2 = 0.44, P < 0.01, respectively). CL did not correlate with total body weight, lean body mass or body surface area. The mean elimination
half-lives of the metabolites M1, M2, M3 and M4 were 11.8 ± 5.0, 21.9 ± 11.8, 19.0 ± 11.3 and 12.3 ± 6.3 h, respectively.
The fractional E
max model produced a much better fit to the relative nadir neutrophil count versus dose data (r
2 = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (C
max) data (r
2 = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion
of patients had a nadir neutrophil count of less than 0.5 × 109/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines
the degree of myelosuppression seems to depend more on the AUC and C
max than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug
exposure expressed as the AUC or C
max.
Received: 18 February 1996 / Accepted: 20 December 1996 相似文献
19.
Dan C. Dimmitt Michael B. Cramer Anther Keung Thangam Arumugham Scott J. Weir 《Cancer chemotherapy and pharmacology》1999,43(2):126-132
Purpose: Dolasetron is a selective 5-HT3 receptor antagonist. The purpose of this study was to determine the effect of cimetidine and rifampin on the steady-state
pharmacokinetics of orally administered dolasetron and its active reduced metabolite, hydrodolasetron. Methods: A group of 18 healthy men (22 to 44 years old) were randomized to receive each of the following three treatments in a three-period
crossover design: 200 mg dolasetron daily (treatment A); 200 mg dolasetron daily plus 300 mg cimetidine four times daily (treatment
B); or 200 mg dolasetron daily plus 600 mg rifampin daily (treatment C). Each study period was separated by a 14-day washout
period. Serial blood samples were collected before the first dose (baseline) on day 1 and at frequent intervals up to 48 h
after the morning dose on day 7 for quantification of dolasetron and its metabolites, hydrodolasetron (both isomers), 5′OH
hydrodolasetron, and 6′OH hydrodolasetron. Serial urine samples were also collected at baseline and during the periods 0–24
and 24–48 h following the morning dose on day 7, and analyzed for dolasetron and its metabolites. Results: Plasma and urine dolasetron concentrations were below quantifiable concentrations for all three treatments. Mean steady-state
area under the plasma concentration-time curve (AUCss(0–24)) of hydrodolasetron increased by 24%, mean apparent clearance (CLapp,po) decreased by 19%, and maximum plasma hydrodolasetron concentration (Cmax,ss) increased by 15% when dolasetron was coadministered with cimetidine. When dolasetron was given with rifampin, mean hydrodolasetron
AUCss(0–24) decreased by 28%, CLapp,po increased by 39%, and hydrodolasetron Cmax,ss decreased by 17%. Small differences were found in mean tmax (0.7 to 0.8 h), CLr (2.0 to 2.6 ml/min per kg), and t1/2 (7.4 to 8.8 h) for hydrodolasetron between treatment periods. Approximately 20% and 2% of the dolasetron dose were excreted
in urine as the R(+) isomer and S(−) isomer of hydrodolasetron, respectively, across all three treatments. Dolasetron mesylate was well tolerated in this study
during all three treatment periods, with the highest incidence of adverse events reported during the control period when dolasetron
mesylate was given alone. Conclusion: Based on the small changes in the pharmacokinetic parameters of dolasetron and its active metabolites, as well as the favorable
safety results, no dosage adjustments for dolasetron mesylate are recommended with concomitant administration of cimetidine
or rifampin.
Received: 10 February 1998 / Accepted: 1 June 1998 相似文献
20.
Janet Martin Stephen M. Stribbling Grace K. Poon Richard H. J. Begent Mark Napier Surinder K. Sharma C. J. Springer 《Cancer chemotherapy and pharmacology》1997,40(3):189-201
Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was
to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase
G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and
elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography
(HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not
in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m2, achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug
could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold
of 3 μM for the “therapeutic window” of 120 min after dosing, but the presence of residual prodrug after the first administration
of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable
inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible
at 18 ± 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place,
but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly
by at least 50% at between 10 and 60 min with a half-life of 36 ± 14 min. Analysis of the plasma extracts by LC/MS indicated
that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites.
Received: 21 July 1996 / Accepted: 20 January 1997 相似文献