Cpiii

CPI-d8, CPIII-d8, and [ 3 H]CPI (4.9 Ci/mmol; .97.5% purity) were synthesized by Bristol Myers Squibb (Princeton, NJ) (Supplemental Fig. 1, A-C). CPI and a In the coadministration groups (i.e., groups 3, 4, 5, and 6), a CPI-d8 solution was administered to each monkey 60 minutes after CsA administration.
b A crossover study design was used, and the same three male cynomolgus monkeys were dosed over a series of six treatments with a 1-week washout between treatments (n = 3). One exception was the group 4 that was repeated because of a dosing mistake (n = 6). CPIII were purchased from Frontier Scientific, Inc. (Logan, UT). CsA, CsA-13 C 2 , d4, RIF, PROB, PYR, and CPI-15 N 4 were purchased from Toronto Research Chemicals (Toronto, ON, Canada). High-performance liquid chromatography grade methanol, acetonitrile, and water were obtained from Fisher Scientific (Fair Lawn, NJ). Formic acid and hydrochloric acid were obtained from EMD Chemicals Inc. (Gibbstown, NJ). CsA oral solution (Neoral, 100 mg/ml) was obtained from Novartis Pharmaceuticals (East Hanover, NJ). Cynomolgus monkey and human plasma that were stripped three times with charcoal were purchased from Bioreclamation IVT (Westbury, NY).

CPI and CPIII were purchased as dihydrochloride salts from Frontier Scientific (Logan, UT). Rifampin, 4bHC, cholesterol, highperformance liquid chromatography (HPLC)-grade methanol, acetonitrile, and water were purchased from Sigma Aldrich (St. Louis, MO). 15 N 4 -CPI (20 nM) and d 3 -RIF were purchased from Toronto Research Chemicals (North York, ON, Canada) and used as the internal standard for CPI bioanalysis. d 8 -CPIII was synthesized at Bristol Myers Squibb Company (Princeton, NJ). The cynomolgus monkey plasma stripped four times with charcoal was purchased from Bioreclamation IVT (Westbury, NY). All other reagents and chemicals used were of the highest grade commercially available.