Biopsy of the first tumour-draining lymph node (sentinel node, SN) is bound to become the procedure of choice in regional staging of melanoma and breast cancer patients. Several radiopharmaceuticals have been developed for lymphoscintigraphy. In this paper we review the most frequently used radiopharmaceuticals for their appropriateness in the sentinel-node procedure. We conclude that accurate localization of SNs is demonstrated using technetium-99m-sulfur colloid ( 99m Tc-SC), 99m Tc antimony trisulfide colloid ( 99m Tc-ATC) [10] and 99m Tc nanocolloidal albumin ( 99m Tc-CA). 99m Tc-Ca and 99m Tc-SC are both available in Europe. In the United States 99m Tc-SC is the only registered tracer for lymphoscintigraphy & k w d : Key words: Sentinel node -99m Tc-sulfur colloid -99m Tcantimony trisulfide colloid -99m Tc-colloidal albumin -Radiocolloids Eur J Nucl Med (1999) 26 (Suppl): S36-S42

Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other 99mTc radiopharmaceuticals, such as 99mTc-tetrofosmin and several 99Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [11C]colchicine, [11C]verapamil and [11C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [11C]colchicine and [11C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[11C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively. Results obtained in MRP2 mutated GY/TR rats have demonstrated visualization of MRP-mediated transport. This tracer permits the study of MRP transport function abnormalities in vivo, e.g. in Dubin-Johnson patients, who are MRP2 gene deficient. Results obtained show the feasibility of using SPET and PET to study the functionality of MDR transporters in vivo.

Summary 9gmTc-sestamibi (SSmTc-MIBI) is a substrate for the P-glycoprotein (P-gp) pump but it is not known whether it is a substrate for the multidrug resistance-associated protein (MRP) pump. Therefore, 99mTc-MIBI was evaluated in the GLC4 cell line and its doxorubicin-resistant MRP-, but not P-gp-, overexpressing GLC4/ADR sublines as well as in the Si cell line and its MRP-transfected subline Sl-MRR 99mTc-MIBI concentration decreased in the GLC4/ADR sublines with increasing MRP overexpression and was lower in S1-MRP than in Si. 99mTc-MIBI plus vincristine increased 99mTc-MIBI concentration in GLC4 lines compared with 99,"Tc-MIBI alone. 99,"Tc-MIBI efflux raised with increasing MRP expression in the GLC4 lines. Glutathione depletion elevated 99mTc-MIBI concentration in GLC4/ADR15,x. Cross resistance for 99Tc-MIBI, used to test cytotoxicity of the Tc compound, was observed in GLC4/ADR,50X vs GLC4. 99Tc-MIBI induced a synergistic effect on vincristine cytotoxicity in GLC4/ADR15oX. These results show that 99mTc-MIBI is involved in MRP-mediated efflux. The fact that 99mTc-MIBI efflux is influenced by MDR1 and MRP expression must be taken into account when this y-rays-emitting complex is tested for tumour efflux measurements.Keywords: multidrug resistance; P-glycoprotein; multidrug resistance-associated protein; 99mTc-sestamibi; drug transportResistance of tumours to chemotherapeutic compounds is an important problem in the clinic. Drugs such as anthracyclines, vinca alkaloids and epipodophyllotoxins are involved in the socalled multidrug resistance (MDR) Bradley et al, 1988;De Vries et al, 1989;De Jong et al, 1990;Meijer et al, 1990;Cole et al, 1992;Versantvoort et al, 1992; Scheper et al, 1993).One of the mechanisms involved in MDR is the overexpression, in tumour cells, of the ATP-dependent 170-kDa P-glycoprotein (P-gp) encoded by the MDR] gene (Endicott and Ling, 1989). P-gp acts as a transmembrane efflux pump that transports chemotherapeutic compounds out of the cell, resulting in drug resistance. P-gp is also expressed in many normal human tissues, such as the liver (bile canaliculi), pancreas, colon, jejunum and kidney (Thiebaut et al, 1987;Sugawara et al, 1988). In normal tissues, P-gp is considered to act as a transporter of toxins.Drugs that are substrates for P-gp are hydrophobic and mostly positively charged at neutral pH. Piwnica-Worms et al (1993) have shown that 99mTc-sestamibi (99mTc-MIBI), a lipophilic cationic radiopharmaceutical, is also a substrate for P-gp-mediated transport (Piwnica-Worms et al, 1993;Vallabhaneni et al, 1994;Ballinger et al, 1995). Consequently, 99-Tc-MIBI allowed visualization of P-gp-mediated efflux in tumours in the animal model (Piwnica-Worms et al, 1993).Apart from P-gp, another pump, the multidrug resistance-associated protein (MRP), is involved in MDR. The MRP pump was identified and characterized as a member of the ATP-binding cassette superfamily (Cole et al, 1992;Ishikawa, 1992 Correspondence to: EGE de Vries 1994). In MRP-transfected cell lines, it was shown that t...

The toxicity and pharmacokinetic properties of a drug determine whether hemodialysis and/or hemoperfusion are indicated in acute intoxications. Valproic acid is considered unremovable by hemodialysis because of the high protein binding of 90%-95%. A 27-year-old male with a history of seizures was admitted to the emergency room because of coma, hypernatriemia, and respiratory failure caused by an intoxication with a large dose of valproic acid. At admission, the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (therapeutic range: 50-100 mg/L (350-700 micromol/ L). The anion gap was 26 mmol/L (normal <12-14 mmol/L) and corresponded fairly well with this valproic acid level. Because of the potential toxicity of this high valproic acid level serial hemodialysis and hemoperfusion was performed. The first session was done with a charcoal column and the second session with a resin column. The patient recovered during the course of treatment. The valproic acid plasma clearances during treatment were: 80 mL/min (hemodialysis); 40 mL/min (hemoperfusion by charcoal) and 80 mL/min (hemoperfusion by resin, only in the first hour). The protein binding of valproic acid in plasma was only 32% at the start and was 54% at the end of the two sessions. In this specific case of a severe valproic acid intoxication, saturated protein binding resulted in an increased fraction of unbound valproic acid. This made hemodialysis an effective treatment, while hemoperfusion was relatively less effective because of saturation of the column. In conclusion, the toxicokinetics of valproate are quite different from the pharmacokinetics at therapeutic levels. The anion gap and protein binding are important parameters in toxicokinetics.

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L-[1-C-11]-tyrosine is a valid tracer for diagnosis of brain tumors and allowed quantification of PSR.

Palivizumab is a humanized, monoclonal antibody used to protect at-risk infants against respiratory syncytial virus (RSV) infection. The regular dosage scheme causes a low initial trough level and accumulation of the antibody after subsequent injections. Using a simple pharmacokinetic model, the authors devised an alternative dosage regimen that might correct these problems while cutting costs by 35%. To spare health care budgets, dosage schemes for future monoclonal antibodies must be chosen carefully.

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