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Gab-jin Park,1 Soo Hyeon Bae,1 Wan-Su Park,1 Seunghoon Han,1 Min-Ho Park,2 Seok-Ho Shin,2 Young G Shin,2 Dong-Seok Yim1,2 1Department of Clinical Pharmacology and Therapeutics, Seoul St Mary’s Hospital, PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, Catholic University of Korea, Seoul, South Korea; 2College of Pharmacy, Chungnam National University, Daejeon, South Korea Purpose: A microdose drug–drug interaction (DDI) study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study. Patients and methods: Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim) and known perpetrators: fluconazole (inhibitor) and rifampin (inducer). For both studies, the microdose (100 µg, cold compound) and the regular dose (20 mg) of omeprazole were given at days 0 and 1, respectively. On days 2–9, the inhibitor or inducer was given daily, and the microdose and regular dose of omeprazole were repeated at days 8 and 9, respectively. Full omeprazole pharmacokinetic samplings were performed at days0, 1, 8, and 9 of both studies for noncompartmental analysis. Results: The magnitude of the DDI, the geometric mean ratios (with perpetrator/omeprazole only) of maximum concentration (Cmax) and area under the curve to the last measurement (AUCt) of the microdose and the regular dose were compared. The geometric mean ratios in the inhibition study were: 2.17 (micro) and 2.68 (regular) for Cmax, and 4.07 (micro), 4.33 (regular) for AUCt. For the induction study, they were 0.26 (micro) and 0.21 (regular) for Cmax, and 0.16 (micro) and 0.15 (regular) for AUCt. There were no significant statistical differences in the magnitudes of DDIs between microdose and regular-dose conditions, regardless of induction or inhibition. Conclusion: Our results may be used as partial evidence that microdose DDI studies may replace regular-dose studies, or at least be used for DDI-screening purposes. Keywords: drug–drug interaction, microdose, CYP2C19

1. The pharmacokinetics and disposition of GDC-0879, a small molecule B-RAF kinase inhibitor, was characterized in mouse, rat, dog, and monkey. 2. In mouse and monkey, clearance (CL) of GDC-0879 was moderate (18.7-24.3 and 14.5 +/- 2.1 ml min(-1) kg(-1), respectively), low in dog (5.84 +/- 1.06 ml min(-1) kg(-1)) and high in rat (86.9 +/- 14.2 ml min(-1) kg(-1)). The volume of distribution across species ranged from 0.49 to 1.9 l kg(-1). Mean terminal half-life values ranged from 0.28 h in rats to 2.97 h in dogs. Absolute oral bioavailability ranged from 18% in dog to 65% in mouse. 3. Plasma protein binding of GDC-0879 in mouse, rat, dog, monkey, and humans ranged from 68.8% to 81.9%. 4. In dog, the major ketone metabolite (G-030748) of GDC-0879 appeared to be formation rate-limited. 5. Based on assessment in dogs, the absorption of GDC-0879 appeared to be sensitive to changes in gut pH, food and salt form (solubililty), with approximately three- to four-fold change in areas under the curve (AUCs) observed.

The degradation product and its stability of deguelin, a naturally occurring rotenoid and potential cancer chemopreventive agent, was evaluated in several vehicles using liquid chromatography‐electrospray mass spectrometry. Deguelin was prepared as a 2 mg/mL solution in acetonitrile, corn oil, yohimbine oil, Tween‐80, Cremophor‐EL, liposomes, and phospholipid micelles, and chemical stability was monitored for 28 days using HPLC‐UV and HPLC‐MS systems coupled to C18 reverse phase columns. Deguelin was stable in acetonitrile, corn oil, and yohimbine oil for 28 days when stored at 4°C. However, it rapidly decomposed in liposomes, Cremophor‐EL, Tween 80, and phospholipid micelles, with daily decay rates of 0.39%, 0.86%, 1.93%, and 2.82%, respectively. The degradation product was determined by physical and spectral data to be tephrosin after isolation by semi‐preparative HPLC. Tephrosin was produced by deguelin auto‐oxidation, and this was likely accelerated by endogenous peroxides found in Cremophor‐...

A rapid and sensitive high performance liquid chromatography-electrospray/MS method has been developed to determine alliin in rat plasma. The method involved deproteinization of these samples with 2.5-volumes (v/w) of acetonitrile/ethanol (1:1) and then 5 μL aliquots of the supernatant were injected onto a amino-silica (NH2) column coupled with an electrospray/MS system. The mobile phase employed isocratic elution with 5% acetonitrile for 10 min; the flow rate was 1.0 mL/min. The column effluent was analyzed by selected ion monitoring (SIM) for the negative pseudo-molecular ion of alliin [M−H]− at m/z 176. The limit of detection for alliin in rat plasma by this method was ca. 10 ng/mL and the accuracy for intra- and inter-assay were between 88.3% and 110.1%. The coefficients of variation of the intra- and inter-assay were generally low (below 9.2% and 11.0%, respectively) for rat plasma. No problems were encounted due to interference from endogenous substances.

A high performance liquid chromatographic method using photoreduction fluorescence detection was described for the analysis of ginsenosides. Ginsenosides were separated on an amino column using acetonitrile and aqueous 2-tert-butylanthraquinone(t-BAQ) solution. Column effluent was passed through a 45cm-PTFE capillary tube coiled around a 10W-UV lamp to reduce t-BAQ to a highly fluorescent dihydroxy anthracene derivative which was detected by a fluorescence detector. The detection limit for the ginsenoside Rg1 by this method was found to be about 130ng. This method is less influenced by other UV-absorbing compounds compared to the conventional HPLC-UV detection method.

GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide) is a potent, selective Hedgehog (Hh) signalling pathway inhibitor being developed for the treatment of various cancers. The in vivo clearance of GDC-0449 was estimated to be 23.0, 4.65, 0.338, and 19.3 ml min(-1) kg(-1) in mouse, rat, dog and monkeys, respectively. The volume of distribution ranged from 0.490 in rats to 1.68 l kg(-1) in mice. Oral bioavailability ranged from 13% in monkeys to 53% in dogs. Predicted human clearance using allometry was 0.096-0.649 ml min(-1) kg(-1) and the predicted volume of distribution was 0.766 l kg(-1). Protein binding was extensive with an unbound fraction less than or equal to 6%, and the blood-to-plasma partition ratio ranged from 0.6 to 0.8 in all species tested. GDC-0449 was metabolically stable in mouse, rat, dog and human hepatocytes and had a more rapid turnover in monkey hepatocytes. Proposed metabolites from exploratory metabolite identification in vitro (rat, dog and human liver microsomes) and in vivo (dog and rat urine) include three primary oxidative metabolites (M1-M3) and three sequential glucuronides (M4-M6). Oxidative metabolites identified in microsomes M1 and M3 were formed primarily by P4503A4/5 (M1) and P4502C9 (M3). GDC-0449 was not a potent inhibitor of P4501A2, P4502B6, P4502D6, and P4503A4/5 with IC50 estimates greater than 20 microM. K(i)'s estimated for P4502C8, P4502C9 and P4502C19 and were 6.0, 5.4 and 24 microM, respectively. An evaluation with Simcyp suggests that GDC-0449 has a low potential of inhibiting P4502C8 and P4502C9. Furthermore, GDC-0449 (15 microM) was not a potent P-glycoprotein/ABCB1 inhibitor in MDR1-MDCK cells. Overall, GDC-0449 has an attractive preclinical profile and is currently in Phase II clinical trials.