Biomedical subjects

J H Schellens

Publications and source records attributed to J H Schellens.

At least 37 records · Page 2Linked to original sources

PubMed2001

Ras biochemistry and farnesyl transferase inhibitors: a literature survey.

Over the last decades, knowledge on the genetic defects involved in tumor formation and growth has increased rapidly. This has launched the development of novel anticancer agents, interfering with the proteins encoded by the identified mutated genes. One gene of particular interest is ras, which is found mutated at high frequency in a number of malignancies. The Ras protein is involved in signal transduction: it passes on stimuli from extracellular factors to the cell nucleus, thereby changing the expression of a number of growth regulating genes. Mutated Ras proteins remain longer in their active form than normal Ras proteins, resulting in an overstimulation of the proliferative pathway. In order to function, Ras proteins must undergo a series of post-translational modifications, the most important of which is farnesylation. Inhibition of Ras can be accomplished through inhibition of farnesyl transferase, the enzyme responsible for this modification. With this aim, a number of agents, designated farnesyl transferase inhibitors (FTIs), have been developed that possess antineoplastic activity. Several of them have recently entered clinical trials. Even though clinical testing is still at an early stage, antitumor activity has been observed. At the same time, knowledge on the biochemical mechanisms through which these drugs exert their activity is expanding. Apart from Ras, they also target other cellular proteins that require farnesylation to become activated, e.g. RhoB. Inhibition of the farnesylation of RhoB results in growth blockade of the exposed tumor cells as well as an increase in the rate of apoptosis. In conclusion, FTIs present a promising class of anticancer agents, acting through biochemical modulation of the tumor cells.

Alkyl and Aryl Transferases↗

PubMed2001

Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel.

Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m(2), as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m(2), at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.

Adult↗

PubMed2001

The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel.

The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m(2) oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.1 microM (T>0.1 microM) of oral paclitaxel. The mean (+/-SD) AUC and T>0.1 microM values of oral paclitaxel with CsA 10 mg/kg were 4.29+/-0.88 microM x h and 12.0+/-2.1 h, respectively. With CsA 5 mg/kg these values were 2.75+/-0.63 microM x h and 7.0+/-2.1 h, respectively (p=0.028 for both parameters). In conclusion, dose reduction of CsA from 10 to 5 mg/kg resulted in a significant decrease in the AUC and T>0.1 microM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC and T>0.1 microM values compared to CsA 15 mg/kg (data which we have published previously), the minimally effective dose of CsA is determined at 10 mg/kg.

Adenocarcinoma↗

PubMed2001

Chemical and enzymatic stability of a cyclic depsipeptide, the novel, marine-derived, anti-cancer agent kahalalide F.

Kahalalide F is a cyclic depsipeptide isolated from the Hawaiian mollusk Elysia rufescens. This compound is under present phase I clinical investigations as an anti-tumor drug. The role of possible metabolic reactions of this drug in (pre-)clinical investigations has not yet been explored. The first results for kahalalide F in this field of research are given in this paper. The chemical degradation of kahalalide F was investigated under acid, neutral and alkaline conditions using high-performance liquid chromatography with ultraviolet detection. The half-lives at 80 degrees C were 1.1, 20 and 8.6 h at pH 0, 1 and 7, respectively. At 26 degrees C and pH 11, the half-life was 1.65 h. At pH 7 and 11, only one reaction product of kahalalide F was observed, kahalalide G, the hydrolyzed lactone product of kahalalide F. At pH 0 and 1, additional reaction products emerged. Metabolic conversion of kahalalide F was tested in vitro using three different enzyme systems based on pooled human microsomes, pooled human plasma and uridine 5'-diphosphoglucuronyl transferase, respectively. The incubated samples were analyzed using the same chromatographic technique as for the degradation samples. Biotransformations were not observed under these conditions and, therefore, it is concluded that kahalalide F is a metabolically stable drug.

Antineoplastic Agents↗

PubMed2001

Population pharmacokinetics and dynamics in phase II studies of the novel bioreductive alkylating cytotoxic indoloquinone EO9.

Population pharmacokinetic-dynamic analysis was prospectively integrated in the clinical phase II programme of EO9 to determine the population pharmacokinetic profile in a larger population of patients, to estimate individual patient pharmacokinetic parameters, and to investigate relationships between drug exposure and clinical outcome. A sparse sampling method was developed, which involved three sampling times, and was implemented during course 1. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, in particular total plasma clearance (CL) of EO9 and area under the curve (AUC). In total, samples were collected of 85 (65%) of the patients. Pharmacokinetic evaluation was successful in 61 (72%) of the sampled patients. CL of EO9 showed substantial variability (median 5.08 l/min; range 2.67-6.42) and was of the same magnitude as in the phase I study where full pharmacokinetic profiles were used. No significant relationships were noticed between exposure parameters and safety, but overall limited toxicity was observed. No tumor responses were documented. Prospective implementation of large-scale population pharmacokinetic-dynamic analysis is feasible and may generate important findings, in particular when tumor responses and relevant toxicity are observed.

Adult↗

PubMed2001

Pharmacokinetics of oral cyclosporin A when co-administered to enhance the oral absorption of paclitaxel.

The objective of this study was to evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the oral absorption of paclitaxel. Patients received oral paclitaxel in doses of 60-360 mg/m(2) in combination with a dose of oral CsA of 15 mg/kg. Dose escalation of paclitaxel from 60 to 300 mg/m(2) resulted in a significant decrease in the area under the concentration-time curve (AUC) of CsA from 24.4+/-9.9 to 17.6+/-2.8 mg/l.h (p=0.03) (n=28). In conclusion, increases in the paclitaxel dose resulted in a decrease in the AUC of CsA. This observation may be explained by the increase in the co-solvent Cremophor EL of paclitaxel causing reduced absorption of CsA.

Absorption↗

PubMed2001

Search for metabolites of ecteinascidin 743, a novel, marine-derived, anti-cancer agent, in man.

Ecteinascidin 743 (ET-743) is a potent anti-tumoral agent of a marine origin. It is currently being tested in phase II clinical trials using a 3-weekly 24-h i.v. infusion of 1500 microg/m(2) and 3-h infusions of 1650 microg/m(2). Knowledge of the metabolism of ET-743 is, however, still scarce. In the present study, a qualitative chromatographic discovery of metabolites of ET-743 in man is reported. ET-743 and its demethylated analog ET-729 were incubated at 37 degrees C in the presence of enzyme systems, pooled human microsomes, pooled human plasma and uridine 5'-diphosphoglucuronyltransferase, respectively, in appropriate media. Reaction products were investigated chromatographically using photodiode array and ion spray-mass spectrometric detection (LC-MS). The main reaction products in microsomal incubations of ET-743 resulted from a remarkable breakdown of the molecule. In plasma the drugs were deacetylated, and the transferase did actually yield a glucuronide of both ET-743 and ET-729. In contrast, screening of urine, plasma and bile, collected from patients treated with ET-743 at the highest dose levels, using a sensitive LC-MS assay, did not result in detection of ET-729 and metabolites which were generated in vitro. The urinary excretion of ET-743 in man was lower than 0.7% of the administered dose for a 24-h infusion.

Antineoplastic Agents, Alkylating↗

PubMed2001

Adaptive intrapatient dose escalation of cisplatin in patients with advanced head and neck cancer.

The purpose of this study was to explore the feasibility and toxicity of intrapatient dose adjustment using predefined levels of exposure to cisplatin, with the ultimate goal to further improve the antitumor activity of the treatment. The primary parameter for adaptive dosing was the level of platinum DNA adducts in peripheral white blood cells (WBC) and the secondary parameter the area under the curve (AUC) of unbound platinum in plasma, which were determined during the applied courses. Target levels had been defined in a previously performed pharmacologic study. The concept of adaptive dosing was tested in 16 patients with locally advanced head and neck (H/N) cancer who would receive six weekly courses of cisplatin at a starting dose level of 80 mg/m(2), which was previously investigated in a phase II study. Forty-seven percent of patients received a dose increase varying from 10 to 40%. Only two patients had exposure levels significantly below the defined target levels for DNA adducts and AUC. The majority of patients reached the defined target levels by modest dose increases of 10-20% during course 2. Relevant but reversible ototoxicity (temporary grade 3 in two patients) and renal toxicity (temporary grade 2 in two other patients) were observed. The pattern and severity of the toxicity was comparable to that encountered in the previous phase II study in H/N cancer patients. We conclude that the strategy of intrapatient dose adjustment for cisplatin is practically feasible in a research setting even when a short turn around time of 1 week is the limit for reporting results. Although in some patients the dose increase that had to be applied to reach target levels was substantial (up to 40%), this approach in H/N cancer patients is not expected to improve the response rate significantly, because these significantly underdosed patients represented only a small percentage of the investigated population. The great majority of patients needed only limited (10-20%) dose increases which very likely will not improve the response rate to a clinically significant extent. The outlined concept is currently being explored in other tumor types and schedules of cisplatin.

Adult↗

PubMed2001

Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites.

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

Animals↗

PubMed2001

Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918.

This study was aimed at characterizing the role of BCRP/MXR/ABCP (BCRP) in resistance of the human ovarian tumor cell lines T8 and MX3 to camptothecins more extensively and investigating whether resistance can be reversed by inhibiting BCRP by GF120918. Camptothecins studied were topotecan, CPT-11, and its active metabolite SN-38, 9-aminocamptothecin, and the novel experimental camptothecins NX211, DX8951f, and BNP1350. Notably, DX8951f and BNP1350 appeared to be very poor substrates for BCRP, with much lower resistance factors observed both in T8 and MX3 cells than observed for the other camptothecins tested. In the presence of a nontoxic dose level of GF120918, the intracellular accumulation of topotecan in the T8 and MX3 cells was completely restored to the intracellular levels observed in the sensitive IGROV1 parental cell line. This resulted in almost complete reversal of drug resistance to topotecan and to most of the other topoisomerase I drugs tested in the T8 cell line and to complete reversal in the MX3 cells. However, coincubation of DX8951f or BNP1350 with GF120918 did not affect the cytotoxicity of either of these drugs significantly. From the combined data, we conclude that the affinities of topoisomerase I drugs for BCRP are, in decreasing order: SN-38 > topotecan > 9-aminocamptothecin approximately CPT-11 > NX211 > DX8951f > BNP1350. Furthermore, GF120918 appears to be a potent reversal agent of BCRP-mediated resistance to camptothecins, with almost complete reversal noted at 100 nM. Potential BCRP-mediated resistance to topoisomerase I inhibitors can also be avoided by using the BCRP-insensitive drugs DX8951f or BNP1350. This observation may have important clinical implications for future development of novel camptothecins.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2001

Influence of dose and infusion duration on pharmacokinetics of ifosfamide and metabolites.

The anticancer drug ifosfamide is a prodrug requiring activation through 4-hydroxyifosfamide to ifosforamide mustard, to exert cytotoxicity. Deactivation of ifosfamide leads to 2- and 3-dechloroethylifosfamide and the release of potentially neurotoxic chloracetaldehyde. The aim of this study was to quantify and to compare the pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide, 4-hydroxyifosfamide, and ifosforamide mustard in short (1-4 h), medium (24-72 h), and long infusion durations (96-240 h) of ifosfamide. An integrated population pharmacokinetic model was used to describe the autoinducible pharmacokinetics of ifosfamide and its four metabolites in 56 patients. The rate by which autoinduction of the metabolism of ifosfamide developed was found to be significantly dependent on the infusion schedule. The rate was 52% lower with long infusion durations compared with short infusion durations. This difference was, however, comparable with its interindividual variability (22%) and was, therefore, considered to be of minor clinical importance. Autoinduction caused a less than proportional increase in the area under the ifosfamide plasma concentration-time curve (AUC) and more than proportional increase in metabolite exposure with increasing ifosfamide dose. During long infusion durations dose-corrected exposures (AUC/D) were significantly decreased for ifosfamide and increased for 3-dechloroethylifosfamide compared with short infusion durations. No differences in dose-normalized exposure to ifosfamide and metabolites were observed between short and medium infusion durations. This study demonstrates that the duration of ifosfamide infusion influences the exposure to the parent and its metabolite 3-dechloroethylifosfamide. The observed dose and infusion duration dependence should be taken into account when modeling ifosfamide metabolism.

Antineoplastic Agents, Alkylating↗

PubMed2000

Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan.

BACKGROUND AND METHODS: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin. To investigate the physiologic role of BCRP, we used polarized mammalian cell lines to determine the direction of BCRP drug transport. We also used the BCRP inhibitor GF120918 to assess the role of BCRP in protecting mice against xenobiotic drugs. Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined. To avoid the confounding drug transport provided by P-glycoprotein (P-gp), the roles of Bcrp1 in the bioavailability of topotecan and the effect of GF120918 were studied in both wild-type and P-gp-deficient mice and their fetuses. RESULTS: Bcrp1 mediated apically directed transport of drugs in polarized cell lines. When both topotecan and GF120918 were administered orally, the bioavailability (i.e., the extent to which a drug becomes available to a target tissue after administration) of topotecan in plasma was dramatically increased in P-gp-deficient mice (greater than sixfold) and wild-type mice (greater than ninefold), compared with the control (i.e., vehicle-treated) mice. Furthermore, treatment with GF120918 decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re-)uptake by the small intestine. In pregnant GF120918-treated, P-gp-deficient mice, relative fetal penetration of topotecan was twofold higher than that in pregnant vehicle-treated mice, suggesting a function for BCRP in the maternal-fetal barrier of the placenta. CONCLUSIONS: Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs. We propose that strategic application of BCRP inhibitors may thus lead to more effective oral chemotherapy with topotecan or other BCRP substrate drugs.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2000

Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone- and topotecan-resistant cell lines.

Tumor cells may display a multidrug resistant phenotype by overexpression of ATP-binding cassette transporters such as multidrug resistance (MDRI) P-glycoprotein, multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). The presence of BCRP has thus far been reported solely using mRNA data. In this study, we describe a BCRP-specific monoclonal antibody, BXP-34, obtained from mice, immunized with mitoxantrone-resistant, BCRP mRNA-positive MCF-7 MR human breast cancer cells. BCRP was detected in BCRP-transfected cells and in several mitoxantrone- and topotecan-selected tumor cell sublines. Pronounced staining of the cell membranes showed that the transporter is mainly present at the plasma membrane. In a panel of human tumors, including primary tumors as well as drug-treated breast cancer and acute myeloid leukemia samples, BCRP was low or undetectable. Extended studies will be required to analyze the possible contribution of BCRP to clinical multidrug resistance.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2000

Validated method for the determination of platinum from a liposomal source (SPI-77) in human plasma using graphite furnace Zeeman atomic absorption spectrometry.

A sensitive analytical method based on flameless atomic absorption spectrometry with Zeeman correction has been validated for the quantitative determination in human plasma of platinum originating from cisplatin in a liposomal source, SPI-77. The performance of the method was acceptable over a sample concentration range of 0. 125-1.25 micromol platinum/L and the lower limit of quantification was determined to be 1.25 micromol platinum/L in undiluted clinical samples. The performance data of the assay were investigated using both a calibration curve with carboplatin in plasma ultrafiltrate and diluted human plasma samples spiked with SPI-77. The recoveries, between-day and the within-day precisions of both methods of calibration were not significantly different allowing carboplatin ultrafiltrate calibration standards to be used to quantify platinum derived from SPI-77 in human plasma. Apparently, the liposomal formulation had no significant influence on the determination of platinum. The usefulness of the presented method was demonstrated in a phase I clinical and pharmacokinetic study. In addition, in vitro experiments were carried out to determine the distribution of SPI-77 in blood. The results indicated that platinum from SPI-77 mainly concentrates in plasma and that binding to and/or endocytosis in red blood cells is negligible.

Antineoplastic Agents↗

PubMed2000

Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion.

Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h intravenous infusion at a dose level of 100 mg/m(2) with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a three-compartment model. The mean area under the curve (AUC) for docetaxel was 3.1 +/- 0.9 h. mg/l and the clearance was 34.8 +/- 9.3 l/h per m(2). There was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected in plasma samples collected 5-30 min after the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most frequently present and was detected in 8 out of 24 patients with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regression analysis was performed to predict M4 docetaxel metabolism. In the final model, alanine aminotransferase and alkaline phosphatase levels were the strongest predictors. No relationship was found between M4 metabolism and percentage decrease in neutrophil count in this study. Three patients with high M4 concentrations in plasma during course 1 suffered from most pronounced fluid retention (grade 2-3) after two to five courses.

Adult↗

PubMed2000

Successful treatment with paclitaxel of a patient with metastatic extra-adrenal pheochromocytoma (paraganglioma). A case report and review of the literature.

This case report describes the history of a patient with an aggressive course of a metastatic extra-adrenal pheochromocytoma (paraganglioma) who received different combination chemotherapy regimens with no or short-lasting clinical benefit. However, during treatment with single-agent paclitaxel, there was a significant clinical improvement, a partial biochemical response and a minor roentgenologic response, which was sustained for 1 year. In this report we present this case and also review the literature on the chemotherapy used for this rare disease over the past 15 years. To enable the activity of paclitaxel against this neoplasm to be determined, more patients need to be treated.

Adult↗

PubMed2000

Modulation of oral bioavailability of anticancer drugs: from mouse to man.

Oral bioavailability of many anticancer drugs is poor and highly variable. This is a major impediment to the development of new generation drugs in oncology, particularly those requiring a chronic treatment schedule, a.o. the farnesyltransferase inhibitors. Limited bioavailability is mainly due to: (1) cytochrome P450 (CYP) activity in gut wall and liver, and (2) drug transporters, such as P-gp in gut wall and liver. Shared substrate drugs are affected by the combined activity of these systems. Available preclinical in vitro and in vivo models are in many cases only poorly predictive for oral drug uptake in patients because of a.o. interspecies differences in CYP drug metabolism and intestinal drug-transporting systems. Clearly, novel systems that allow reliable translation of preclinical results to the clinic are strongly needed. Our previous work, also using P-gp knockout (KO) mice, already showed that P-gp has a major effect on the oral bioavailability of several drugs and that blockers of P-gp can drastically improve oral bioavailability of paclitaxel and other drugs in mice and humans (Schinkel et al., Cell 77 (1994) 491; Sparreboom et al., Proc. Natl. Acad, Sci. USA 94 (1997) 2031; Meerum Terwogt et al. Lancet 352 (1998) 285). This work revealed, however, that apart from P-gp other drug-transporting systems and CYP effects also determine overall oral drug uptake. The taxanes paclitaxel and docetaxel are considered excellent substrate drugs to test the concept that by inhibition of P-gp in the gut wall and CYP activity in gut wall and/or liver low oral bioavailability can be increased substantially. In current studies we focus on the development of chronic oral treatment schedules with these drugs and on other drug transport systems that may play a significant role in regulation of oral bioavailability of other classes of (anti-cancer) drugs. The current review paper describes the background and summarizes our recent results of modulation of oral bioavailability of poorly available drugs, focused on drug transport systems and CYP in gut wall and liver.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

The oral route for the administration of cytotoxic drugs: strategies to increase the efficiency and consistency of drug delivery.

There is an increasing interest to administer cytotoxic drugs to patients by the oral route. Quality of life issues, treatment advantages and pharmaco-economics are major arguments in favor of oral therapy. However, low or moderate bioavailability in combination with considerable interpatient variability are frequently observed which may reduce the feasibility of the oral route for this class of drugs with a generally narrow therapeutic window. Until recently, investigators focused on absorption enhancers which slightly damage the intestinal surface such as salicylates, methylxanthines and surfactants to improve the oral bioavailability of drugs. To date, a shift can be seen towards more subtle mechanisms to enhance the absorption. This review article focuses on two important mechanisms that determine the oral bioavailability of cytotoxic drugs. These include the presence of drug transporters in the intestinal epithelium pumping drugs into the intestinal lumen, such as MDR1 type P-glycoproteins, and first-pass elimination by cytochrome P450 isoenzymes (e.g. 3A4 and 3A5) or other enzymes in the intestines and/or liver. Currently preclinical and clinical studies are being performed to explore the feasibility of blocking these transporters/enzymes in order to achieve higher and less variable systemic drug levels after oral dosing. This review gives an update of the results of these studies. It is concluded however, that further research to unravel the processes involved in oral drug uptake is warranted to make the oral route a more efficient and consistent way of drug administration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗