ABSTRACT:Lapatinib is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing human epidermal receptor 2 (ErbB2). This work investigated the role of P-glycoprotein (Pgp; the protein from the Mdr1a/b gene) and breast cancer resistance protein (Bcrp; the protein from the Bcrp1 gene) in modulating the central nervous system penetration of lapatinib at steady-state conditions in FVBn mice (wild-type), Mdr1a/b(؊/؊), Bcrp1(؊/؊), and Mdr1a/b(؊/؊)/ Bcrp1(؊/؊) knockout mice. After an intravenous infusion of lapatinib for 24 h to a targeted steady-state plasma concentration of 700 ng/ml (0.3 mg/kg/h) or 7000 ng/ml (3 mg/kg/h), lapatinib brainto-plasma ratios were approximately 3-to 4-fold higher in Mdr1a/ b(؊/؊) knockout mice (ratio range from 0.09 to 0.16) compared with wild-type mice (ratio range from 0.03 to 0.04). There was no difference in the brain-to-plasma ratio in the Bcrp1(؊/؊) knockout mice (ratio range from 0.03 to 0.04) compared with wild-type mice. In contrast, Mdr1a/b(؊/؊)/Bcrp1(؊/؊) triple knockout mice had a 40-fold higher brain-to-plasma ratio (ratio range from 1.2 to 1.7), suggesting that Pgp and Bcrp work in concert to limit the brainto-plasma ratio of lapatinib in mice. This finding has important potential consequences for the treatment of brain tumors in breast cancer patients treated with tyrosine kinase inhibitors as well as the basic understanding of ATP binding cassette transporters expressed in the blood-brain barrier on the central nervous system disposition of drugs.Lapatinib (Tykerb, GW572016) is a novel member of the 4-anilinoquinazoline class of tyrosine kinase inhibitors (TKI) (Boyd et al., 2005;Johnston and Leary, 2006;Moy and Goss, 2006). It is a dual inhibitor of both epidermal growth factor receptor (ErbB) 1 and human epidermal receptor (HER) 2 with IC 50 values of approximately 10 nM against the purified receptors in vitro, and it potently inhibits growth of epidermal growth factor receptor and/or HER2-overexpressing tumors both in vitro and in vivo. Lapatinib is approved for use in combination with other anticancer agents for the treatment of HER2-positive breast cancers (Geyer et al., 2006).A particular challenge to the treatment of breast cancer, particularly HER2-overexpressing tumors, is central nervous system (CNS) metastases. Up to 35% of patients with HER2-positive advanced breast cancer relapse due to intracranial disease, despite control of the peripheral tumors (Weil et al., 2005). CNS tumors are difficult to treat due to limited brain and/or tumor exposure of most anticancer agents. Nonclinical data suggest that the brain concentrations of lapatinib and other TKIs are low due to efflux transporters in the blood-brain barrier (Heimberger et al., 2002;Breedveld et al., 2005;Kil et al., 2007;Polli et al., 2008). These nonclinical data imply that TKIs may have limited Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.108.024646. La...

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ABSTRACT(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gramnegative infections. In this study, six healthy adult male subjects received a single i.v. dose of [ 14 C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite.

Since the acute toxicity of nitrobenzene (NB) in rats has not been characterized, experiments were performed to ascertain the possible deleterious effects of NB in different tissues of the male Fischer-344 rat. Rats were given single oral doses of NB(50-450 mg/kg) and at the time of sacrifice, 25 tissues were removed and examined histologically by light microscopy. Histopathological changes induced by a single oral dose of NB consistently involved only the liver and testes. One rat receiving 450 mg NB/kg had a microscopic cerebellar lesion. Hepatic centrolobular necrosis appeared inconsistently in rats given various doses of NB, while hepatocellular nucleolar enlargement was consistently detected in rats given doses of NB as low as 110 mg/kg. These data suggest that nucleolar enlargement was independent of cell death and subsequent regeneration. Testicular lesions were confined to the seminiferous tubules and consisted of necrosis of the primary and secondary spermatocytes with the appearance of multinucleated giant cells between one and four days after administration of NB 300 mg/kg. Necrotic debris and decreased numbers of spermatozoa were seen in the epididymis as early as three days after NB administration. The NB-induced methemoglobinemia does not appear to be solely responsible for the formation of early lesions in the rat liver, testes, or brain, since sodium nitrite administration, at dosages which produced methemoglobinemia equivalent to that of NB, did not produce any histopathological changes. Thus, the observed fiver and testicular damage are probably due to a direct effect of NB or its metabolites.