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1.
Kato A Ueyama J Abe F Hotta K Tsukiyama I Oshima T Kondo F Saito H Hasegawa T 《Anticancer research》2011,31(9):2915-2922
The present study has investigated the effect of panipenem, a widely used antibiotic, on the pharmacokinetics of an active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxy-camptothecin (SN-38) and SN-38 glucuronide (SN-38G) produced by uridine-diphosphate glucuronosyltransferase (UGT) 1A isoform-mediated glucuronidation in rats. Rats received a 1 h infusion with panipenem at a loading dose of 10 mg/kg and a maintenance dose of 15 mg/min/kg once a day for 5 days. When the effect of pretreatment with panipenem on glucuronidation activities of substrates for hepatic UGT1A isoforms was investigated using substrates 4-methylumbelliferone (4MU), estradiol and SN-38, the rate of 4MU glucuronide formation was significantly increased, but that of estradiol glucuronide formation was unchanged. However, the rate of SN-38G formation showed a tendency to increase. One hour after the final infusion of panipenem or saline, SN-38 (2 mg/kg) was administered intravenously in rats with or without bile duct cannulation. Pretreatment with panipenem had no effect on the plasma concentration-time curves and biliary excretion of SN-38 and SN-38G in rats with and without bile duct cannulation. There were also no significant differences in the relative extent of glucuronidation of SN-38 to SN-38G (AUC(2 h, SN-38G)/AUC(2 h, SN-38)) between panipenem-treated and untreated rats. These findings suggest that pretreatment with panipenem does not alter the pharmacokinetics of SN-38 and SN-38G, suggesting the possibility that panipenem can be used safely for cancer patients undergoing irinotecan chemotherapy. 相似文献
2.
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
3.
Clinton F. Stewart William C. Zamboni William R. Crom Peter J. Houghton 《Cancer chemotherapy and pharmacology》1997,40(3):259-265
The present study was conducted to quantitate the disposition of irinotecan lactone and its active metabolite SN-38 lactone
in mice following oral and intravenous administration, and to evaluate the systemic exposure of irinotecan lactone and SN-38
lactone associated with antitumor doses of irinotecan lactone in mice bearing human tumor xenografts. Nontumor-bearing mice
were given a single oral or intravenous irinotecan dose (5, 10, 40, or 75 mg/kg), and serial plasma samples were subsequently
obtained. Irinotecan and SN-38 lactone plasma concentrations were measured using an isocratic HPLC assay with fluorescence
detection. The disposition of intravenous irinotecan lactone was modeled using a two-compartment pharmacokinetic model, and
the disposition of oral irinotecan and SN-38 lactone was modeled with noncompartmental methods. Irinotecan lactone showed
biphasic plasma disposition following intravenous dosing with a terminal half-life ranging between 1.1 to 3 h. Irinotecan
lactone disposition was linear at lower doses (5 and 10 mg/kg), but at 40 mg/kg irinotecan lactone clearance decreased and
a nonlinear increase in irinotecan lactone AUC was observed. The steady-state volume of distribution ranged from 19.1 to 48.1
l/m2. After oral dosing, peak irinotecan and SN-38 lactone concentrations occurred within 1 h, and the irinotecan lactone bioavailability
was 0.12 at 10 mg/kg and 0.21 at 40 mg/kg. The percent unbound SN-38 lactone in murine plasma at 1000 ng/ml was 3.4 ± 0.67%,
whereas at 100 ng/ml the percent unbound was 1.18 ± 0.14%. Irinotecan and SN-38 lactone AUCs in micebearing human neuroblastoma
xenografts were greater than in nontumor-bearing animals. Systemic exposure to unbound SN-38 lactone in nontumor-bearing animals
after a single oral irinotecan dose of 40, 10, and 5 mg/kg was 28.3, 8.6, and 2.9 ng h/ml, respectively. Data from the present
study provide important information for the design of phase I studies of oral irinotecan.
Received: 30 August 1996 / Accepted: 27 November 1996 相似文献
4.
Yong Liu Jacqueline Ramírez Larry House Mark J. Ratain 《European journal of cancer (Oxford, England : 1990)》2010,46(11):2097-2103
The combination of irinotecan and erlotinib has been evaluated in clinical trials, although toxicity has been significant. We aimed to investigate the effect of erlotinib on SN-38 glucuronidation and the association between UGT1A polymorphisms and SN-38 glucuronidation activity in the presence of erlotinib. The inhibitory effect of erlotinib on SN-38 glucuronidation was determined by measuring the formation rates for SN-38 glucuronide, using recombinant human UGT1A1, pooled human liver microsomes (HLMs) and 52 Caucasian liver microsomes in the absence or presence of erlotinib. Inhibition kinetic studies were conducted. AUC ratios were used to predict the risk of potential drug–drug interactions (DDI) in vivo. Our data showed that erlotinib exhibited potent non-competitive inhibition against SN-38 glucuronidation in pooled HLMs and UGT1A1. Using the physiological and pharmacokinetic parameters obtained from the literature, we estimated the in vivo concentrations of unbound erlotinib available for UGT1A1 active site and thus the AUC ratios of SN-38 were also quantitatively predicted. It is estimated that erlotinib administered at 50 mg/day or higher doses may result in at least a 24% increase in SN-38 AUC. Significant correlations were observed between SN-38 glucuronidation activity in the presence of erlotinib and UGT1A1128 in 52 Caucasian liver microsomes. Our results suggest that erlotinib is a potent inhibitor of SN-38 glucuronidation via UGT1A1 inhibition. The coadministration of erlotinib with irinotecan may result in clinically significant DDI. UGT1A1128 polymorphism correlates with erlotinib’s effect on SN-38 glucuronidation. The present findings shed light on the development and optimisation of combinations involving irinotecan and erlotinib. 相似文献
5.
Rouits E Charasson V Pétain A Boisdron-Celle M Delord JP Fonck M Laurand A Poirier AL Morel A Chatelut E Robert J Gamelin E 《British journal of cancer》2008,99(8):1239-1245
This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan. 相似文献
6.
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
7.
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
8.
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
9.
The modulation of irinotecan-induced diarrhoea and pharmacokinetics by three different classes of pharmacologic agents 总被引:1,自引:0,他引:1
Diarrhoea is the major dose-limiting toxicity of irinotecan hydrochloride (CPT-11) in the clinical setting. This study was designed to evaluate the effects of different pharmacological agents in the modulation of CPT-11 induced diarrhoea in Sprague-Dawley rats. We studied the effects of intravenous valproic acid (VPA), ceftriaxone (CTX) and oral charcoal in the modulation of CPT-11 induced diarrhoea. Male Sprague-Dawley rats (n=7 per group) were given CPT-11 60 mg/kg as intravenous injection from day 1 to 5 (total dose 300 mg/kg) in all treatment groups. Group 1 (G1) rats only received CPT-11, group 2 to 6 (G2 to G6) rats received in addition to IV CPT-11 60 mg/kg, IV valproic acid (VPA) 200 mg/kg (G2), IV VPA 200 mg/kg + IV ceftriaxone (CTX) 100 mg/kg (G3), IV VPA 200 mg/kg + oral activated charcoal 250 mg administered twice daily (G4), IV CTX 100 mg/kg (G5) and oral charcoal 250 mg every 12 hourly (G6). We compared the pharmacokinetics of total CPT-11 and its metabolites and the frequency and grade of diarrhoea in each group of rats. There were no significant differences in the pharmacokinetic parameters of total CPT-11 between treatment groups (p>0.05). Cotreatment with CTX and charcoal resulted in a lower total SN-38G AUC0- infinity (p<0.05 and p<0.01, respectively). Cotreatment with CTX also resulted in a lower Cmax for total SN-38G compared to other groups (p<0.01). A higher frequency of grade 3 diarrhoea was observed in G1 rats compared to other groups. Co-treatment with VPA (log OR: -1.13; 95% CI: -1.85, -0.41) or CTX (log OR: -1.66; 95% CI: -2.43, -0.88) were found to be associated with a lower odds of grade 3 diarrhoea compared to control or charcoal treated groups. Our findings indicate that CPT-11 treated rats given VPA and CTX, either alone or in combination has similar effects in preventing high grade diarrhoea. Activated charcoal was not found to be effective in the prevention of high grade diarrhoea. 相似文献
10.
Hironori Iwasaki Takafumi Okabe Kensaku Takara Yasuhiko Yoshida Kaoru Hanashiro Hirosuke Oku 《Cancer chemotherapy and pharmacology》2010,65(5):953-959
Purpose
This study examined the pharmacokinetics of irinotecan (CPT-11), active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide (SN-38G) amrubicin (AMR), and active metabolite amrubicinol (AMR-OH) after intravenous administration of this combination therapy in rats.Methods
Male Sprague-Dawley rats were treated with 10 mg/kg CPT-11 with 10 mg/kg AMR. AMR, AMR-OH, CPT-11, SN-38 and SN-38G were measured in plasma, bile, and tissues using high-performance liquid chromatography.Results
Co-administration of CPT-11 resulted in a significant decrease in plasma concentrations and area under the curves (AUC) of AMR-OH compared with treatment with AMR alone. On the other hand, co-administration of AMR resulted in a slight increase in the initial plasma concentration of SN-38; however, there were no differences in AUC values in CPT-11 and SN-38. The cumulative biliary excretion curves of AMR, CPT-11, and their active metabolites were not changed. CPT-11 inhibited the conversion of AMR to AMR-OH in rat cytosolic fractions.Conclusions
CPT-11 did not affect the pharmacokinetic of AMR but decreased the plasma concentration of AMR-OH and might affect the formation of AMR-OH from AMR in hepatocytes. 相似文献11.
Purpose: The major pharmacokinetic parameters of unchanged cisplatin (CDDP) related to nephrotoxicity were evaluated in rats in vivo
using a pharmacodynamic model. Methods: CDDP was administered according to various dosing schedules (single bolus, intermittent bolus, or continuous infusion).
Unchanged CDDP in plasma and urine was quantified using high-performance liquid chromatography (HPLC). The pharmacokinetics
were assessed by model-independent methods. The relationship between pharmacokinetics and BUN levels was evaluated using a
sigmoid maximum response (Emax) model. Results: Unchanged CDDP showed linear pharmacokinetics after single bolus injections of 1 to 5 mg/kg CDDP. Nephrotoxicity was ameliorated
following intermittent bolus injection (1 mg/kg per day for 5 days) and continuous infusions (over 2 and 3 h) of the same
CDDP doses (5 mg/kg), although these dosing schedules did not change the area under the concentration-time curve (AUC), total
clearance (Clt), urinary excretion of unchanged CDDP or kidney platinum levels significantly. The maximum BUN level, as a
nephrotoxicity marker, showed dose-related increases after single bolus injection of 1 to 5 mg/kg CDDP and after 3-h infusion
of 5 to 25 mg/kg. The pharmacodynamic relationship between the maximum BUN level and Cmax and between the maximum BUN level and AUC were apparently different between single bolus injection and 3-h infusion. The
maximum BUN level was related to the AUC calculated by plasma concentrations of unchanged CDDP greater than the threshold
level (AUC>Cmin), a relationship most successfully described by the signoid Emax model, regardless of CDDP dose and schedule. The plasma threshold level of unchanged CDDP was determined as 0.9 μgPt/ml in
rats. Conclusions: The present results substantiated the importance of C×T (AUC) value as an indicator of CDDP-induced nephrotoxicity in vivo
as well as of tumor cell-killing effect of CDDP in vitro. The AUC>Cmin of unchanged CDDP was found to be an important pharmacokinetic parameter predicting CDDP nephrotoxicity.
Received: 12 February 1996 / Accepted: 5 September 1996 相似文献
12.
Wei Peng Yong Jacqueline Ramirez Federico Innocenti Mark J Ratain 《Clinical cancer research》2005,11(18):6699-6704
PURPOSE: Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam. Its effect on UGT1A substrates is unclear. A recent study found that coadministration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38 (7-ethyl-10-hydroxycamptothecine), an UGT1A substrate. This study investigates whether ketoconazole contributes to the increase in SN-38 formation by inhibiting SN-38 glucuronidation. EXPERIMENTAL DESIGN: SN-38 glucuronidation activities were determined by measuring the rate of SN-38 glucuronide (SN-38G) formation using pooled human liver microsomes and cDNA-expressed UGT1A isoforms (1A1, 1A7 and 1A9) in the presence of ketoconazole. Indinavir, a known UGT1A1 inhibitor, was used as a positive control. SN-38G formation was measured by high-performance liquid chromatograph. RESULTS: Ketoconazole competitively inhibited SN-38 glucuronidation. Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9. The K(i) values were 3.3 +/- 0.8 micromol/L for UGT1A1 and 31.9 +/- 3.3 micromol/L for UGT1A9. CONCLUSIONS: These results show that ketoconazole is a potent UGT1A1 inhibitor, which seems the basis for increased exposure to SN-38 when coadministered with irinotecan. 相似文献
13.
Thompson PA Gupta M Rosner GL Yu A Barrett J Bomgaars L Bernstein ML Blaney SM Mondick J 《Cancer chemotherapy and pharmacology》2008,62(6):1027-1037
Objective To develop a population pharmacokinetic model of irinotecan and its major metabolites in children with cancer and to identify
covariates that predict variability in disposition.
Methods A population pharmacokinetic model was developed using plasma concentration data from 82 patients participating in a multicenter
Pediatric Oncology Group (POG) single agent phase II clinical trial. Patients between 1 and 21 years of age with solid tumors
refractory to standard therapy received irinotecan, 50 mg/m2, as a 60-min intravenous infusion for 5 consecutive days every 3 weeks. Blood samples were collected and analyzed for irinotecan
and three metabolites (SN-38, SN-38G, and APC). The population model was developed with NONMEM. Clearance and volume were
scaled allometrically using corrected body weight. Exponential error models were used to describe the interindividual variance
in pharmacokinetic parameters, and the residual error was described with a proportional model. Significant covariate effects
were identified graphically using S-PLUS and were added to the base-model. The final model was evaluated by simulating data
from two other POG trials.
Results The best structural model for irinotecan and its metabolites consisted of six-compartments: two compartments for irinotecan
and SN-38, and one each for APC and SN-38G. Age and bilirubin were found to be significant covariates affecting SN-38 clearance.
SN-38 clearance was greater in patients less than 10 years of age and lower in patients with a total serum bilirubin >0.6 mg/dL.
Simulations revealed that the model was able to predict drug and metabolite exposure (AUC) for patients receiving the same
or similar doses (30–65 mg/m2) of irinotecan.
Conclusions This population model accurately describes the pharmacokinetics of irinotecan and its primary metabolites. The model, which
includes age and bilirubin as covariate effects on SN-38 clearance, is the first population model to describe the pharmacokinetics
of irinotecan and its major metabolites in children.
Supported in part by: NICHD 5 U10 HD037242-09, NIH M01 RR000188-43, NCI U01 CA57745, NCI U10 CA98453, NCRR M01 RR00188-37,
The Mitchell Ross Children’s Cancer Fund, Pharmacia/Upjohn. 相似文献
14.
Onoue M Kurita A Kado S Matsumoto T Kaneda N Uchida K Kato I Yokokura T 《Cancer chemotherapy and pharmacology》2008,61(4):595-605
We assessed the involvement of UDP-glucuronosyltransferase (UGT) activity in episodes of irinotecan hydrochloride (CPT-11)-induced
delayed-onset diarrhea using a mutant rat strain with an inherited deficiency of UGT1A (Gunn rats). Gunn rats exhibited severe
diarrhea after the intravenous administration of CPT-11 at a dose of 20 mg/kg, whereas Wistar rats did not. In the epithelium
of the small intestine and cecum in Gunn rats, the shortening of villi, degeneration of crypts, and destruction of the nucleus
were observed. The AUC, MRT, and t
1/2 of CPT-11, and the AUC of 7-ethyl-10-hydroxycamptothecin (SN-38) in plasma were, respectively, 1.6-fold, 1.5-fold, 1.7-fold,
and 6.5-fold higher, and the cumulative biliary excretion rate of SN-38 was 2.3-fold higher, in Gunn rats than Wistar rats.
SN-38 glucuronide excreted via bile in Wistar rats was not de-conjugated in the small intestinal lumen. The SN-38 AUC values
in small intestinal tissues were also 5.0 to 5.8-fold higher in Gunn rats than Wistar rats. In conclusion, Gunn rats developed
severe delayed-onset diarrhea after i.v. administration of CPT-11 at a much lower dose. Severe intestinal impairments would
be induced in Gunn rats through exposure to SN-38 at high levels for a long period mainly via the intestinal lumen and partially
via the bloodstream. These results clarified that the deficiency of UGT activity contributed greatly to the induction of the
CPT-11-induced delayed-onset diarrhea and epithelial impairment in the intestine. In the clinic, great care is needed when
using chemotherapy with CPT-11 in patients with poor UGT activity. 相似文献
15.
Poujol S Pinguet F Ychou M Abderrahim AG Duffour J Bressolle FM 《Oncology reports》2007,18(6):1613-1321
In this study we propose for the first time a limited sampling strategy to estimate the individual pharmacokinetic parameters of both irinotecan and SN-38 in patients treated with the irinotecan plus 5-fluorouracil (FOLFIRI) regimen. The pharmacokinetics of irinotecan and SN-38 were studied in 74 patients with advanced inoperable digestive cancer. Plasma concentrations were taken during and up to the 42 h following a 90-min infusion of irinotecan (180-225 mg/m(2)). Data splitting was used to create model-building and validation data sets, and data were analysed with the NONMEM program. The disposition of SN-38 was dependent on the disposition of irinotecan. The estimated pharmacokinetic parameters of irinotecan [terminal half-life (t(1/2)), 11.5 h; total clearance (CL), 25.0 l h(-1); area under curve (AUC), 14.9 mg x h l(-1)] and SN-38 (terminal t(1/2), 32.2 h; AUC, 0.42 mg x h l(-1)) were similar to those determined in other studies. The protocol involving two sampling times, at 1 and 24 h following the beginning of the infusion, allowed for a precise and accurate determination of the individual pharmacokinetic parameters of the two drugs. The limited sampling strategy developed in this study ought to facilitate future studies on the pharmacology and toxicity of irinotecan-based therapy. 相似文献
16.
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
17.
M. L. Rothenberg J. G. Kuhn L. J. Schaaf G. I. Rodriguez S. G. Eckhardt M. A. Villalona-Calero D. A. Rinaldi L. A. Hammond S. Hodges A. Sharma G. L. Elfring R. G. Petit P. K. Locker L. L. Miller D. D. von Hoff 《Annals of oncology》2001,12(11):1631-1641
Objectives:This trial was performed to determine themaximum tolerated dose (MTD), dose-limiting toxicity (DLT), andpharmacokinetic profile of irinotecan (CPT-11) when administered on aonce-every-2-week schedule.
Patients and methods:CPT-11was administered to successive cohorts of patients at progressivelyincreasing starting doses ranging from 125 to 350 mg/m2. TheMTD and DLTs were determined both for CPT-11 alone and for CPT-11followed by filgrastim (G-CSF). Plasma samples were obtained during thefirst 24 hours after initial dosing to determine the totalconcentrations (lactone + carboxylate forms) of CPT-11; of theactive metabolite SN-38; and of SN-38 glucuronide (SN-38G).
Results:Neutropenic fever was the DLT for CPT-11 atthe 300 mg/m2 dose level. When G-CSF was added, doseescalation beyond 350 mg/m2 could not be achieved due tograde 2–3 toxicities that prevented on-time retreatment withCPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasmaconcentrations of SN-38 and SN-38G were approximately 2.5% and4.2% of the corresponding peak plasma concentration for CPT-11,respectively. The harmonic mean terminal half-lives for CPT-11, SN-38,and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. Nopredictive correlation was observed between CPT-11 or SN-38 peakconcentration or AUC and first-cycle diarrhea, neutropenia, nausea, orvomiting. Across the range of doses studied, mean CPT-11 clearance was14.0 ± 4.0 l/h/m2 and volume of distribution was 146± 45.9 l/m2.
Conclusions:Whenadministered every two weeks, the recommended phase II starting dose ofCPT-11 is 250 mg/m2 when given alone and 300 mg/m2when supported by G-CSF. This every-two-week regimen offers a tolerableand active alternative to weekly or every-three-week single-agent CPT-11therapy. 相似文献
18.
Allegrini G Di Paolo A Cerri E Cupini S Amatori F Masi G Danesi R Marcucci L Bocci G Del Tacca M Falcone A 《Cancer chemotherapy and pharmacology》2006,58(5):585-593
Purpose: Recent clinical studies have demonstrated a reduction of irinotecan (CPT-11) gastrointestinal toxicities when the CPT-11 is administered in combination with thalidomide in patients with diagnosis of colorectal cancer. The main purpose of this study was to investigate possible interactions between CPT-11 pharmacokinetics and thalidomide to explain the previously described gastrointestinal toxicity reduction. Methods: In our clinical trial, advanced cancer patients were treated with CPT-11 on a dose of 350 mg/m2 at day 1 every 3 weeks. Only at the first cycle, CPT-11 was administered in association with thalidomide on a dose of 400 mg/day given from day 1 to day 14. From the second cycle, the treatment was continued with irinotecan alone at the same dose. Pharmacokinetics analysis of irinotecan and its metabolites, SN-38 and SN-38-glucuronide, were performed at the first and second cycle. Results: A total of 19 patients entered the study. The pharmacokinetic analysis were performed on 16 patients. Pharmacokinetic data suggested a decreased metabolism of irinotecan into SN-38 and SN-38-glucuronide when it was administered with thalidomide. Indeed, area under the time–concentration curve (AUC) of SN-38 was significantly lower at the first cycle than the second cycle (0.99±0.45 h×μg/ml vs 1.34±0.65, respectively, P=0.027) whereas AUC of irinotecan and SN-38-glucuronide were higher at first cycle than second cycle (34.53±11.38 h×μg/ml vs. 28.42±12.23 h×μg/ml, P=0.064 and 2.39±1.21 h(μg/ml vs. 1.86±1.11 h×μg/ml, P=0.018, respectively). Conclusions: Our study demonstrates a significant decreased metabolism of CPT-11 into the active metabolite SN-38 when CPT-11 is administered in association with thalidomide. These observations strongly suggest an interaction of thalidomide with CPT-11 metabolism and, at least in part, it might explain the previously described improvement in tolerability.Grant support: The work was partially supported by Associazione Italiana Ricerca Cancro (AIRC) and Fondazione A.R.C.O. 相似文献
19.
Araki K Fujita K Ando Y Nagashima F Yamamoto W Endo H Miya T Kodama K Narabayashi M Sasaki Y 《Cancer science》2006,97(11):1255-1259
Pharmacogenetic testing for UDP-glucuronosyltransferase (UGT) 1A1*28, a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan-associated toxicity. We studied the clinical significance of UGT1A1*6 and UGT1A1*27, two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m(2). Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration-time curve (AUC) of the active metabolite of irinotecan (SN-38) to that of SN-38 glucuronide (SN-38G), used as a surrogate for UGT1A1 activity (AUC(SN-38)/AUC(SN-38G)). No patient was homozygous for UGT1A1*28, and none had UGT1A1*27. Two were heterozygous for UGT1A1*28. Two were homozygous and 15 heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6, present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the two patients homozygous for UGT1A1*6 had significantly higher AUC(SN-38)/AUC(SN-38G) ratios than the others (P = 0.0039). Concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1*6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1*28 to more accurately predict irinotecan-related toxicity, at least in Asian patients. 相似文献
20.
Pitot HC Adjei AA Reid JM Sloan JA Atherton PJ Rubin J Alberts SR Duncan BA Denis L Schaaf LJ Yin D Sharma A McGovren P Miller LL Erlichman C 《Cancer chemotherapy and pharmacology》2006,58(2):165-172
Purpose: Intravenous (i.v.) irinotecan is a cytotoxic topoisomerase I inhibitor with broad clinical activity in metastatic colorectal cancer and other tumors. The development of an oral formulation of irinotecan could enhance convenience and lessen the expense of palliative irinotecan delivery. This phase I study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of irinotecan given as a powder-filled capsule (PFC) daily for 5 days every 3 weeks. Patients and methods: Patients with advanced solid tumors received escalating doses of oral irinotecan daily for 5 days every 3 weeks. Plasma samples were collected following the first and fifth doses of irinotecan during Cycle 1 to determine the PK of irinotecan and its major circulating metabolites: SN-38, SN-38G, and APC. Results: 20 patients (median age 61.5 years, range 40–75; M/F 12/8; ECOG PS 0=5, 1=11, 2=4) received oral irinotecan at dose levels of 30 (n=3), 40 (n=3), 50 (n=6), and 60 (n=8) mg/m2/day. Of the eight patients enrolled at 60 mg/m2, three patients experienced DLT (≥ grade 3) consisting of nausea (three patients), vomiting (three patients), diarrhea (two patients), and febrile neutropenia (two patients) for which all the three patients required hospitalization. Treatment of six patients at the 50-mg/m2 dose level resulted in no DLT. Other toxicities observed include abdominal pain, alopecia, anorexia, and asthenia. After oral administration, irinotecan was rapidly absorbed into systemic circulation and converted to the active metabolite SN-38. Increasing dose levels resulted in a dose-dependent increase in mean exposure parameters (Cmax and AUC) of irinotecan and metabolites. Systemic exposure parameters (Cmax and AUC0-24) of irinotecan and SN-38 were comparable between days 1 and 5. The extent of conversion from irinotecan to SN-38 was approximately threefold higher after the oral administration compared to that previously observed after i.v. administration. The exposure parameters of irinotecan or SN-38 are of limited value in predicting severity of Cycle 1 toxicities in the twofold dose range evaluated. Conclusion: Daily oral administration of irinotecan as the PFC formulation for 5 days every 3 weeks can safely deliver protracted exposure to SN-38, with the MTD of 50 mg/m2/d.Supported in part by Pharmacia and National Cancer Institute Grants U01-CA69912, M01-RR00585, and CA15083-26 相似文献