No abstract

Three paramagnetic heterobimetallic lantern complexes of the form [PtM(tba) 4 (OH 2 )] (M ¼ Fe, 1; Co, 2; Ni, 3; tba ¼ thiobenzoate) have been prepared in a single-step, bench-top procedure. In all three cases, a lantern structure with Pt-M bonding is observed in solution and in the solid state. Compound 1 is a monomer whereas 3 exists as a dimer in the solid state via a Pt/Pt metallophilic interaction. Compound 2 has been characterized in forms with (2a, purple) and without (2b, yellow) Pt/Pt metallophilic interactions. The dimers 2a (J ¼ À10 cm À1 , based on the spin Hamiltonian Ĥ ¼ À2J (S A $S B )) and 3 (J ¼ À60 cm À1 ) exhibit antiferromagnetic coupling between the two first-row metal ions in the solid state via a Pt/Pt non-covalent metallophilic interaction. The electronic structure ofNi, units have been studied with DFT calculations, confirming the relative spin-state energies observed and the antiferromagnetic exchange pathway through four d z 2 orbitals. The compounds 2a and 3 are the first examples of antiferromagnetic coupling through an unbridged M/M contact.

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC 50 ) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (V max ) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m 2 of pemetrexed supplemented with folic acid and vitamin B 12 , recovered the clinical data adequately. The observed/predicted increases in C max and the area under the plasma-concentration time curve (AUC 0-inf ) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC 0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.

Hepatic OATPs 1B1, 1B3 and 2B1, as well as P-gp, play important roles in regulating liver uptake and biliary excretion of drugs. The intrinsic ethnic variability in OATP1B1-mediated hepatic uptake of statins has been proposed to underlie the ethnic variability in plasma exposures of statins between Caucasians and Asians. Using a targeted quantitative proteomic approach, we determined hepatic protein concentrations of OATP1B1, OATP1B3, OATP2B1, P-gp, and PMCA4 (a housekeeping protein) in a panel of human livers (n = 141) and compared protein expression across Caucasian, Asian, African-American, and unidentified donors. Using an optimized protocol that included sodium deoxycholate as a membrane protein solubilizer, the hepatic protein expression levels (mean ± S.D.) of these transporters across all livers were determined to be 15.0 ± 6.0, 16.1 ± 8.1, 4.1 ± 1.3, 0.6 ± 0.2, and 2.4 ± 1.0 fmol/μg of total membrane protein, respectively. The scaling factor was 3.5 mg of total membrane protein in 100 mg of wet liver tissue. OATP1B1 protein expression was significantly associated with the c.388A>G (rs2306283, N130D) single nucleotide polymorphism. When compared across ethnicity, the hepatic expression levels of OATP1B1 and OATP1B3 were unexpectedly higher in Asians relative to Caucasians, suggesting that hepatic OATP expression alone does not explain the increased systemic statin levels in Asians compared with Caucasians. These findings may help improve physiologically based pharmacokinetic modeling to predict statin pharmacokinetic profiles and enable extrapolation of pharmacokinetic data of OATP substrates across ethnic groups.