Advances in the use of milk thistle (Silybum marianum)

Milk thistle (Silybum marianum) is an herbal supplement used to treat liver and biliary disorders. Silymarin, a mixture of flavanoid complexes, is the active component that protects liver and kidney cells from toxic effects of drugs, including chemotherapy. Although milk thistle has not significantly altered the course of chronic liver disease, it has reduced liver enzyme levels and demonstrated anti-inflammatory and T cell-modulating effects. There is strong preclinical evidence for silymarin's hepatoprotective and anticarcinogenic effects, including inhibition of cancer cell growth in human prostate, skin, breast, and cervical cells. Milk thistle is considered safe and well-tolerated, with gastrointestinal upset, a mild laxative effect, and rare allergic reaction being the only adverse events reported when taken within the recommended dose range. More clinical trials of rigorous methodology, using standardized and well-defined products and dosages, are needed to evaluate the potential of silymarin against liver toxicity, chronic liver disease, and human cancers.     

Review of clinical trials evaluating safety and efficacy of milk thistle (Silybum marianum [L.] Gaertn.)

Milk thistle extracts have been used as traditional herbal remedies for almost 2000 years. The extracts are still widely used to protect the liver against toxins and to control chronic liver diseases. Recent experimental and clinical studies suggest that milk thistle extracts also have anticancer, antidiabetic, and cardioprotective effects. This article reviews clinical trials of milk thistle conducted in the past 5 years including pharmacokinetic and toxicity studies, herb-drug interactions, and other safety issues. Several trials have studied the effects of milk thistle for patients with liver diseases, cancer, hepatitis C, HIV, diabetes, and hypercholesterolemia. Promising results have been reported in the protective effect of milk thistle in certain types of cancer, and ongoing trials will provide more evidence about this effect. In addition, new established doses and improvement on the quality and standardization of this herb will provide the much-awaited evidence about the efficacy of milk thistle in the treatment of liver diseases. Milk thistle extracts are known to be safe and well tolerated, and toxic or adverse effects observed in the reviewed clinical trials seem to be minimal. The future of milk thistle research is promising, and high-quality randomized clinical trials on milk thistle versus placebo may be needed to further demonstrate the safety and efficacy of this herb.     

Clinical applications of Silybum marianum in oncology

Milk thistle (Silybum marianum) is an herb that is increasingly used in oncology research and treatment settings. Historically, it has been used to treat liver and biliary disorders and has been used in detoxification and cleansing protocols. However, milk thistle is increasingly being investigated for its use in adult and pediatric populations for oncology indications. Possible indications during cancer treatment include cleansing and detoxification after chemotherapy, preventing hepatotoxicity during chemotherapy, treating hepatotoxicity after chemotherapy, and potentiating chemotherapy and radiation therapy as an adjunctive treatment. Milk thistle may also have applications in ameliorating long-term hepatic and cardiovascular effects of cancer treatment. Preliminary studies are investigating its use as a chemopreventive agent and possibly to treat cancer directly. Much of milk thistle's current clinical use grows out of historical uses but is informed by an increasing number of clinical trials and animal studies. This article provides an overview of the current clinical applications of milk thistle in the oncology setting, including guidelines on commonly used forms and doses.     

Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells

Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds. In contrast, silibinin is composed only of a 1:1 mixture of silybin A and silybin B. With these isomers now isolated in quantities sufficient for biological studies, each pure compound was assessed for antiproliferative activities against LNCaP, DU145, and PC3 human prostate carcinoma cell lines. Isosilybin B was the most consistently potent suppressor of cell growth relative to either the other pure constituents or the commercial extracts. Isosilybin A and isosilybin B were also the most effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIalpha gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective. These findings are significant in that isosilybin B composes no more than 5% of silymarin and is absent from silibinin. Whereas several other more abundant flavonolignans do ultimately influence the same end points at higher exposure concentrations, these findings are suggestive that extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment.     

Future directions for research on Silybum marianum for cancer patients

Silymarin (Silybum marianum [L.] Gaertn. [Asteraceae]) is a promising agent for cancer prevention, adjuvant cancer treatment, and reduction of iatrogenic toxicity. Although it is safe and free of serious adverse side effects, few studies have evaluated its use alongside conventional cytotoxic therapies, and adverse events associated with long-term administration are uncertain. Although it may prevent some types of cancer, its promotion of tissue regeneration and its potential estrogen activity could promote the growth of some tumors. Further clinical trials using authenticated fractions of silymarin as simple and complex derivatives are required prior to any general recommendations. Future research should focus on authentication of active chemicals, pharmacokinetics, adverse interactions and quality control, prevention of cancer initiation and progression, adjuvant therapy for specific cancers, and prevention of toxicity from anticancer therapies.     

Antimicrobial and Histological Data Effect of Silybum marianum and Suaeda vermiculata Against Doxorubicin Induced Toxicity in Male Rats

Objective: Silybum marianum and Suaeda vermiculata are popular plants wealthy in cancer prevention agents. There is no enough research on both plants since they are not available in many places. They are widely spread in Egypt. Methods: This research was performed to estimate their antimicrobial effect as well as their hepatoprotective effect against strong drugs inducing oxidative stress such as doxorubicin which may be a chemotherapeutic operator utilized to treat different sorts of cancer and demonstrated to be hepatotoxic medicate. Six bunches of male Wistar rats were utilized (control, Silybum marianum extricate, Suaeda vermiculata extricate, doxorubicin, Silybum marianum extricate additionally doxorubicin and Suaeda vermiculata extricate additionally doxorubicin). Results: Our data confirmed the effective antimicrobial effect of both plants and also the hepatoprotective effect against oxidative damage. Both plants are highly recommended as natural supplements by patients treated by different drugs inducing oxidative stress whereas; Milk thistle was proved to be stronger hepatoprotective herb.     

Clinical pharmacokinetics and metabolism of irinotecan (CPT-11).

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent.     

Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma

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.     

Clinical pharmacokinetics of irinotecan and its metabolites: a population analysis.

PURPOSE: To build population pharmacokinetic (PK) models for irinotecan (CPT-11) and its currently identified metabolites. PATIENTS AND METHODS: Seventy cancer patients (24 women and 46 men) received 90-minute intravenous infusions of CPT-11 in the dose range of 175 to 300 mg/m(2). The PK models were developed to describe plasma concentration profiles of the lactone and carboxylate forms of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38) and the total forms of SN-38 glucuronide (SN-38G), 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC) by using NONMEM. RESULTS: The interconversion between the lactone and carboxylate forms of CPT-11 was relatively rapid, with an equilibration half-life of 14 minutes in the central compartment and hydrolysis occurring at a rate five times faster than lactonization. The same interconversion also occurred in peripheral compartments. CPT-11 lactone had extensive tissue distribution (steady-state volume of distribution [Vss], 445 L) compared with the carboxylate form (Vss, 78 L, excluding peripherally formed CPT-11 carboxylate). Clearance (CL) was higher for the lactone form (74.3 L/h) compared with the carboxylate form (12.3 L/h). During metabolite data modeling, goodness of fit indicated a preference of SN-38 and NPC to be formed out of the lactone form of CPT-11, whereas APC could be modeled best by presuming formation from CPT-11 carboxylate. The interconversion between SN-38 lactone and carboxylate was slower than that of CPT-11, with the lactone form dominating at equilibrium. The CLs for SN-38 lactone and carboxylate were similar, but the lactone form had more extensive tissue distribution. CONCLUSION: Plasma data of CPT-11 and metabolites could be adequately described by this compartmental model, which may be useful in predicting the time courses, including interindividual variability, of all characterized substances after intravenous administrations of CPT-11.     

Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study

Background

Omeprazole is one of the most prescribed medications worldwide and within the class of proton pump inhibitors, it is most frequently associated with drug interactions. In vitro studies have shown that omeprazole can alter the function of metabolic enzymes and transporters that are involved in the metabolism of irinotecan, such as uridine diphosphate glucuronosyltransferase subfamily 1A1 (UGT1A1), cytochrome P-450 enzymes subfamily 3A (CYP3A) and ATP-binding cassette drug-transporter G2 (ABCG2). In this open-label cross-over study we investigated the effects of omeprazole on the pharmacokinetics and toxicities of irinotecan.

Methods

Fourteen patients were treated with single agent irinotecan (600 mg i.v., 90 min) followed 3 weeks later by a second cycle with concurrent use of omeprazole 40 mg once daily, which was started 2 weeks prior to the second cycle. Plasma samples were obtained up to 55 h after infusion and analysed for irinotecan and its metabolites 7-ethyl-10-hydroxycampothecin (SN-38), SN-38-glucuronide (SN-38G), 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC) and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC) by high-performance liquid chromatography (HPLC). Non-compartmental modelling was performed. Toxicities were monitored during both cycles. Paired statistical tests were performed with SPSS.

Results

The exposure to irinotecan and its metabolites was not significantly different between both cycles. Neither were there significant differences in the absolute nadir and percentage decrease of WBC and ANC, nor on the incidence and severity of neutropenia, febrile neutropenia, diarrhoea, nausea and vomiting when irinotecan was combined with omeprazole.

Conclusion

Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan. This widely used drug can, therefore, be safely administered during a 3-weekly single agent irinotecan schedule.     

Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy.

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.     

Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel

OBJECTIVE: To date, data regarding the potential of cannabinoids to modulate cytochrome P450 isozyme 3A (CYP3A) activity are contradictory. Recently, a standardized medicinal cannabis product was introduced in The Netherlands. We anticipated an increased use of medicinal cannabis concurrent with anticancer drugs, and undertook a drug-interaction study to evaluate the effect of concomitant medicinal cannabis on the pharmacokinetics of irinotecan and docetaxel, both subject to CYP3A-mediated biotransformation. PATIENTS AND METHODS: Twenty-four cancer patients were treated with i.v. irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal cannabis (200 ml herbal tea, 1 g/l) for 15 consecutive days, starting 12 days before the second treatment. Blood samples were obtained up to 55 hours after dosing and analyzed for irinotecan and its metabolites (SN-38, SN-38G), respectively, or docetaxel. Pharmacokinetic analyses were performed during both treatments. Results are reported as the mean ratio (95% confidence interval [CI]) of the observed pharmacokinetic parameters with and without concomitant medicinal cannabis. RESULTS: Medicinal cannabis administration did not significantly influence exposure to and clearance of irinotecan (1.04; CI, 0.96-1.11 and 0.97; CI, 0.90-1.05, respectively) or docetaxel (1.11; CI, 0.94-1.28 and 0.95; CI, 0.82-1.08, respectively). CONCLUSION: Coadministration of medicinal cannabis, as herbal tea, in cancer patients treated with irinotecan or docetaxel does not significantly influence the plasma pharmacokinetics of these drugs. The evaluated variety of medicinal cannabis can be administered concomitantly with both anticancer agents without dose adjustments.     

Influence of garlic (Allium sativum) on the pharmacokinetics of docetaxel.

PURPOSE: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients. Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity. This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate. EXPERIMENTAL DESIGN: Women with metastatic breast cancer were treated with docetaxel (30 mg/m(2)) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations. RESULTS: In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m(2) [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m(2) (95% CI, 15.5-31.8) and 20.0 L/h/m(2) (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian). CONCLUSIONS: This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.     

Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials*

BACKGROUND: Irinotecan (CPT-11) is a novel water-soluble camptothecin derivativeselected for clinical testing based on its good in vitro andin vivo activity in various experimental systems, includingpleiotropic drug-resistant tumors. Its mechanism of action appearsmediated through topoiso-merase I inhibition. The purpose ofthis study was to describe CPT-11 and active metabolite SN-38population pharmacokinetics, examine patient characteristicsthat may influence pharmacokinetics, and to investigate pharmacokinetic-phar-macodynamicrelationships that may prove useful in the future clinical managementof this drug. PATIENTS AND METHODS: As part of 3 Phase I studies including 235 patients, pharmacokineticsof CPT-11 and metabolite SN-38 were determined in 107 patients.CPT-11 was administered as a 30-min i.v. infusion accordingto 3 different schedules: daily for 3 consecutive days every3 weeks, weekly for 3 weeks, and once every 3 weeks. Patientscharacteristics were the following: median age 53 years; men,45 women; 105 Caucasians, 2 blacks; performance status was 0–1in 96 patients; tumor sites were predominantly colon, rectum,head and neck, lung, ovary and breast; with the exception of6 patients, all had been previously treated with surgery, chemotherapyand/or radiotherapy. CPT-11 and metabolite SN-38 were simultaneouslydetermined by HPLC using fluorescence detection. Pharmacokineticparameters were determined using model-independent and model-dependentanalyses. RESULTS: 168 pharmacokinetic data sets were obtained in 107 patients(97 first courses, 43 second courses, 23 third courses, 4 fourthcourses, and 1 fifth course). Rebound concentrations of CPT-11were frequently observed at about 0.5 to 1 h following the endof the i.v. infusion, which is suggestive of enterohepatic recyclingof the drug. Model-independent analysis yielded the followingmean population pharmacokinetic parameters for CPT-11: a terminalhalf-life of 10.8 h, a mean residence time (MRT) of 10.7 h,a volume of distribution at stedy state (Vdss) of 150 L/m²,and a total body clearance of 14.3 L/m²/h. Model-dependent analysisdisclosed a CPT-11 plasma disposition as either biphasic ortri-phasic with a mean terminal half-life of 12.0 h. The volumeof distribution Vdss (150 L/m²) and total body clearance (14.8L/m²/h) yielded almost identical values to the above model-independentanalysis. The active metabolite SN-38 presented rebound concentrationsin many courses at about 1 h following the end of the i.v. infusionwhich is suggestive of enterohepatic recycling. The mean timeat which SN-38 maximum concentrations was reached was at 1 hsince the beginning of the 0.5 h infusion (i.e., 0.5 h posti.v.). SN-38 plasma decay followed closely that of the parentcompound with a mean apparent terminal half-life of 10.6 h.Mean 24 h CPT-11 urinary excretion represented 16.7% of theadministered dose, whereas metabolite SN-38 recovery in urinewas minimal (0.23% of the CPT-11 dose). The number of CPT-11treatments did not influence pharmacokinetic parameters of eitherthe parent compound or metabolite SN-38. Although CPT-11 pharmacokineticspresented an important interpatient variability, both CPT-11maximum concentrations (Cmax) and the CPT-11 area under theplasma concentration versus time curves (AUC) increased proportionallyand linearly with dosage (Cmax, r=0.78, p<0.001); CPT-11AUC, r=0.88, p<0.001). An increase in half-life and MRT wasobserved at higher dosages, although this did not influencethe linear increase in AUC as a function of dose. The volumeof distribution at steady state (Vdss) and the total body clearance(CL) were not affected by the CPT-11 dose. Metabolite SN-38AUC increased proportionally to the CPT-11 dose (r=0.67, p<0.001)and also with the parent compound AUC (r=0.75, p<0.001).The increase in dose did not lead to a change in the fractionof drug metabolized into SN-38 (percentage SN-38 AUC/CPT-11AUC = mean value of 3.08%. There was also no significant influenceof CPT-11 dose on the 24-h percent recovery of the parent compoundor of its metabolite in urine. Patient physio-pathological characteristics were examined aspossible determinant of pharmacokinetics. No detectable relationshipwas observed between CL or the metabolic ratio (% SN-38 AUC/CPT-11AUC), with the following physio-pathological factors: age, sex,height, weight, body surface, tumor type, or renal function.However, with regard to hepatic function, significant correlations(negative) were observed with CPT-11 CL and some hepatic functionmarkers, e.g., bilirubinemia and gamma-glutamyl transpeptidase.Also of interest, a significant positive correlation betweenthe metabolic ratio and some liver function parameters wereobserved, e.g., bilirubinemia, aspartate transferase (AST),and alanine transferase (ALT). For the pharmacokinetic-pharmacodynamic studies, CPT-11 AUCcorrelated significantly with the percent decrease of eitherthe white blood cells or the neutrophils. CPT-11 AUC also correlatedsignificantly with the intensity of diarrhea, and the intensityof nausea and vomiting. CPT-11 CL correlated negatively withthe intensity of the principal toxicities observed. MetaboliteSN-38 AUC was also significantly correlated with the percentdecrease in white blood cells and neutrophils. Significant correlationswere also observed between SN-38 AUC and the intensity of diarrhea,and the intensity of nausea and vomiting. The metabolic ratiodid not correlate with any of the principal toxicities encounteredin these clinical studies. With regard to antitumor responses,although the optimal schedule and dose were not obviously definedat the beginning of these phase I trials, 17 tumor responseswere nevertheless observed (2 complete, 9 partial, 6 minor).The observation that most of these responses were obtained atthe highest doses administered is highly suggestive of a dose-responserelationship with this drug. CONCLUSIONS: These data indicate that CPT-11 population pharmacokineticsis linear within the large dose range investigated, that thenumber of treatments do not influence pharmacokinetics, thatliver function affects CPT-11 clearance. Also of interest, theintensity of the major toxicities encountered with this drug(e.g., leukoneutropenia, diarrhea, nausea and vomiting) correlatedwith the exposure (AUC) to CPT-11 and metabolite SN-38. A dose-effectrelationship was also noted for anticancer activity since mosttumor responses were observed at the highest doses administered.These pharmacological data are of importance for the conductof future clinical studies with this active drug.     

The effect of thalidomide on the pharmacokinetics of irinotecan and metabolites in advanced solid tumor patients

Purpose  

Irinotecan and thalidomide are commonly administered antineoplastic drugs. Combination treatment may potentiate their antitumor effect and protect against irinotecan’s intestinal toxicity. We investigated whether thalidomide can modulate the pharmacokinetics of irinotecan and metabolites.     

Influence of hydralazine on the pharmacokinetics of tauromustine (TCNU) in mice.

Several investigators including ourselves have shown that hydralazine can potentiate the anti-tumour activity of certain agents against murine tumours probably by manipulating tumour blood flow. In order to investigate the effects of administration of hydralazine on systemic and tumour drug concentrations, we have examined the plasma and tissue pharmacokinetics of the recently developed nitrosourea, Tauromustine (TCNU). The effect of hydralazine on glomerular filtration rate (GFR) in mice was also examined using inulin single injection plasma clearance. An active dose of TCNU (30 mg kg-1) was administered intravenously into non-tumour bearing NMRI mice or mice bearing MAC 15A or MAC 26 subcutaneous tumours. Plasma and tissue levels of TCNU were measured by HPLC. Hydralazine significantly increased (P less than .005 in all cases) the AUCs and decreased the plasma clearance of the drug. Inulin plasma clearance was decreased from 0.258 +/- 0.046 ml min-1 to 0.096 +/- 0.017 ml min-1 (a factor of 2.69) after administration of hydralazine. This decrease in GFR would explain the increased plasma half-lives of a renally cleared drug. It is likely that the increased AUC values are partly responsible for the improved anti-tumour activity of TCNU when administered with hydralazine, but the impact of these findings on toxicity needs to be established.     

Clinical pharmacokinetics of the irinotecan metabolite 4-piperidinopiperidine and its possible clinical importance

Purpose: To investigate the clinical relevance of 4-piperidinopiperidine (4PP) in the activity of irinotecan (CPT-11), a high-performance liquid chromatography-turboionspray-tandem mass spectrometry assay for plasma 4PP was developed. Methods: Plasma samples were prepared for analysis following C18 solid-phase extraction. Chromatography was performed on a Waters Nova-Pak Phenyl column. Selected reaction monitoring with the mass transitions m/z 169.2 → 84.2 and 139.2 → 98.1 was used for the detection of 4PP and the internal standard (IS), 1-piperidineproprionitrile, respectively. Results: The assay was linear from 14.8 to 591.0 nM with absolute recoveries of 4PP (59.1 nM) and IS (143.7 nM) of 85.7% (n=10) and 86.7% (n=10), respectively. The accuracy and imprecision of the method (total) was ≥96.8% and ≤8.5% over the concentration range studied, respectively. 4PP was detectable in plasma following the administration of 125, 350, 500 mg/m² and 600 mg/m² CPT-11 to patients, with AUC_4PP correlated with the dose (r ²= 0.66). Plasma concentrations of 4PP declined slowly with a long terminal half-life (33.4 ± 17.1 h). Conclusions: Overall, the concentrations of 4PP in plasma were in the sub-micromolar range (<206.9 nM) and substantially lower than those capable of inducing apoptosis of cancer cells. Received: 29 March 1999 / Accepted: 19 July 1999     

Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients.

PURPOSE: To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan's maximum-tolerated dose (MTD). PATIENTS AND METHODS: Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle. RESULTS: Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P <.05) when irinotecan preceded 5-FU. CONCLUSION: The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.