Drug targeting is one of the promising approaches to increase the pharmacological activity of various kinds of therapeutic agents with a concomitant decrease in their unexpected side effects. To optimize the pharmacokinetic property of drug targeting vectors, pharmacokinetic analaysis should be important. Physiologically-based pharmacokinetic (PBPK) model has widely been established for various types of small molecules although such model analysis on macromolecules is still limited. PBPK model analysis can quantitatively describe the disposition of therapeutic agents. Several indices have been defined to characterize the drug targeting efficiency, and the feature of each index can be understood based on PBPK model. Sensitivity analysis based on PBPK model can reveal the most important factors affecting their pharmacological and/or toxicological effects. The other advantage of the PBPK model analysis includes the quantitative prediction of the biodistribution in humans based on the in vitro data. This review will summarize the importance of pharmacokinetic analaysis in the various aspects regarding the design of drug targeting vectors. Several examples for such approach will also be introduced and discussed.

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Many potential CNS active agents, including peptides, proteins, antibodies, and gene medicines, do not readily enter brain from blood, owing to poor permeability through the blood-brain barrier (BBB). The successful delivery of these agents through the BBB in vivo is closely linked to knowledge of pharmacokinetics and transport mechanism at the brain capillary endothelium. In this review, we discuss brain delivery strategies of peptides and proteins from view points of pharmacokinetics and BBB transport mechanism. In addition, this review summarizes recent information regarding the transport system of peptides and proteins. Furthermore, some novel technologies for BBB delivery strategies are introduced in the last part of the review.

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The clearance of colloidal particles from the blood circulation occurs mainly in the liver, spleen and bone marrow by phagocytes lining blood sinuses in these organs of the reticuloendothelial system (RES). The relative distribution of the injected particles in these organs depends on various factors such as the size, surface properties of the injected particles and also the type of serum proteins adsorbed onto the surface of particles. Proteins that adsorb onto the surface of a particle promoting their phagocytosis are termed opsonins. On the other hand, it has been suggested that certain classes of liposomes and pathogenic microorganisms can attract suppressive substances termed dysopsonins from plasma or serum, thereby minimizing the interaction with phagocytes. From these points of view, it is very important to identify the serum opsonins or dysopsonins and to elucidate the uptake mechanisms of the particulate carrier used for the handling of the in vivo disposition of the drug loaded. We believe that understanding of these regulatory mechanisms may provide an opportunity to target or avoid particulate drug carriers into a specific organ of RES.

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An objective of DDS in cancer chemotherapy is to find methods by which anticancer agents selectively target solid tumors. Two main concepts constitute selective tumor targeting, active targeting and passive targeting. The former involves monoclonal antibodies or ligands to tumor related receptors which can target the tumor by utilizing specific binding ability between the antibody and antigen or between the ligand and its receptor. The latter system can be achieved by the so-called “EPR effect, the enhanced permeability and retention effect”. Regarding passive targeting, doxil, a pegylated liposomal doxorubicin, received Food and Drug Administration approval for Kaposi's sarcoma or ovarian cancer. Recent clinical trials including phase III randomized trial have shown clear clinical benefits of doxil. In comparison to doxorubicin, doxil has a significantly smaller volume of distribution, larger AUC, slower clearance, and longer elimination half-life. These different pharmacokinetic profiles likely contribute to the different toxicity profiles and improved therapeutic benefit observed with doxil. NK 911 is a doxorubicin entrapped in a polymer micelle. A phase I clinical trial of NK 911 has just initiated in the National Cancer Center. Miceller encapsulated taxol, KRN 5500 or cisplatin have been developed recently. These will be also evaluated in clinical trials in the near future.

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Antibody-based therapeutics are coming of age. This enthusiasm has stemmed from advances in recombinant technology allowing for the production of chimeric and humarinized antibodies. Recent progress and further application on clinical use of therapeutic antibodies for malignancy were reviewed. The Japan Ministry of Health, Labor and Welfare (MHLW) has approved two of these antibodies, trastuzmab and rituximab in 2001. Trazttizumab has been approved for HER 2-positive metastatic breast cancer and rituximab for relapsed or refractory CD 20-positive indolent or follicular lymphoma. Safety profile of these unconjugated antibodies are generally comfortable, mainly with first-infusion-related symptoms. But tumor-lysis syndrome for rituximab and cardiotoxicity for trastuzmab should be carefully monitored. A chemoimmunoconjugate containing an and-CD 33 antibody and chaliclieamicin has also been approved for relapsed elderly patients with CD 33-positive acute myeloid leukemia in USA, and is now being developed in Japan. Radioimmunoconjugates directed CD 20 demonstrate significant clinical activity in Western countries. For one of these drugs, ⁹⁰Y-ibritumoxnab, the clinical trial is planned to be conducted in Japan also. Novel effective monoclonal antibody-based therapies for malignancy might change “the state of the art” in the treatment. The optimal sequence or combination of antibody-based therapy with chemotherapy awaits defnition in clinical trials.

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Iontophoretic transdermal absorption of a series of β-biockers (atenolol, pindolol, metoprolol, acebutolol, oxprenolol, propranolol) was investigated by measuring the drug concentration in the skin. The objective of this study was to determine the effects of drug properties on the enhancement of drug concentration in the skin by iontophoretic delivery. Anodal iontophoresis of β-blocker was carried out by applying a constant direct current (0.5 mA/0.8 cm², 30 min) to the drug solution (1 mg/mL), placed on the abdominal skin of anesthetized rat, and the drug concentration in the skin was measured by HPLC analysis. The enhancement effect of iontophoresis, represented as a ratio of drug concentration in the skin after iontophoresis to that after passive diffusion (without current), was exponentially attenuated with an increase in drug lipophilicity (the logarithm of 1-octanol/water partition coefficient at pH 7.4). On the other hand, when plotted against polar surface area (PSA) of drug molecule, the iontophoretic enhancement was linearly increased with increasing the PSA. The latter result implied that the transdermal absorption of drug having a strong interaction with water molecule was raised by iontophoresis. As a result, this study demonstrated that the PSA might be a useful parameter for clarifying the mechanism of iontophoretic enhancement and for optimizing the molecular structure of drug candidate to the iontophoretic delivery.

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