Two mixed-valence Mn(III)Mn(II) complexes and a homo-valence Mn(II) trinuclear manganese complex of stoichiometry Mn(III)Mn(II)Mn(III)(5-Cl-Hsaladhp)(2)(AcO)(4)(MeOH)(2).4CH(3)OH (1a), Mn(III)Mn(II)Mn(III) (Hsaladhp)(2)(AcO)(2)(5-Cl-Sal)(2)(thf)(2) (3a) and Mn(II)Mn(II)Mn(II) (AcO)(6)(pybim)(2) (1b) where H(3)saladhp is a tridentate Schiff base ligand and pybim a neutral bidentate donor ligand, have been structurally characterized by using X-ray crystallography. The structurally characterized mixed-valence complexes have strictly 180 degrees Mn(III)-Mn(II)-Mn(III) angles as required by crystallographic inversion symmetry. The complexes are valence trapped with two terminal Mn(III) ions showing Jahn-Teller distortion along the acetate or salicylate-Mn(III)-X axis. The Mn.Mn separation is 3.511 Å and 3.507 Å respectively. The mixed-valence complexes have S = (3)/(2) ground state and the homovalence complex S = (5)/(2), with small antiferromagnetic exchange J couplings, -5.6 and -1.8 cm(-1), respectively, while the powder ESR spectra at 4 K show a broad low field signal with g approximately 4.3 for Mn(III)Mn(II)Mn(III) and a broad temperature-dependent signal at g = 2 for Mn(II)Mn(II)Mn(II). Crystal data for 1a: [C(36)H(60)O(20)N(2)Cl(2)Mn(3)], triclinic, space group P&onemacr;, a = 9.272(7) Å, b = 11.046(8) Å, c = 12.635(9) Å, alpha = 76.78(2) degrees, beta = 81.84(2) degrees, gamma = 85.90(2) degrees, Z = 1. Crystal data for 3a: [C(48)H(56)O(18)N(2)Cl(2)Mn(3)], monoclinic, space group P2(1)/n, a = 8.776(3) Å, b = 22.182(7) Å, c = 13.575(4) Å, beta = 94.44(1) degrees, Z = 2. Crystal data for 1b: [C(36)H(36)O(12)N(6)Mn(3)], triclinic, space group P&onemacr;, a = 13.345(6) Å, b = 8.514(4) Å, c = 9.494(4) Å, alpha = 75.48(1) degrees, beta = 75.83(1) degrees, gamma = 76.42(1) degrees, Z = 1.

This study showed the presence of a pharmacokinetic interaction that led to higher plasma concentrations of PLD when combined with paclitaxel and to a minor extent when combined with docetaxel. This pharmacokinetic information may be of value when planning combination therapies of PLD with taxanes.

The aim of this study is to investigate the feasibility and determine the pharmacokinetics of low-dose paclitaxel in cancer patients with severe hepatic dysfunction. This was a prospective study. Patients with liver metastases who had either transaminase serum levels higher than 10 times the upper normal limit or bilirubin serum levels higher than 5 times the upper normal limit were eligible. All patients underwent pharmacokinetic evaluation during the first course of treatment. Pharmacokinetics in severe hepatic dysfunction patients were compared with data from a reference group of patients with normal hepatic function who participated in a phase I study. Nine severe hepatic dysfunction patients were treated with paclitaxel 70 mg/m administered as a 1-h infusion every 2 weeks. They received a median three treatment courses (range 1-9) without clinically relevant toxicity. The area under the concentration-time curve of paclitaxel was markedly higher in severe hepatic dysfunction patients when compared with the normal hepatic function control group treated with the same dose (98% increase, P<0.001). Area under the concentration-time curve and the time above 0.1 micromol/l (T>0.1) concentration threshold in the severe hepatic dysfunction patients who received paclitaxel 70 mg/m approximated pharmacokinetics of paclitaxel in patients with normal liver function who received 130 mg/m. Maximum plasma concentration (Cmax) did not differ between the two groups. In conclusion, paclitaxel 70 mg/m was safely delivered every 2 weeks in patients with severe hepatic dysfunction and resulted in adequate plasma concentrations. Paclitaxel at this dosage can be taken as an option for severe hepatic dysfunction patients who are expected to get clinical benefits from taxanes.