Pharmacokinetics,dose proportionality and permeability of S002-333 and its enantiomers,a potent antithrombotic agent,in rabbits

Abstract

1.?S002-333 [(2-(4′-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide)] is a novel and potent antithrombotic active agent. The present work investigates the pharmacokinetics, bioavailability, dose proportionality and permeability of the racemate, S002-333 in male New Zealand White (NZW) rabbits.

2.?Rabbits were administered single intravenous (i.v.) (2?mg/kg) and three oral doses of 10, 20 and 40?mg/kg of S002-333, respectively, at different occasions to evaluate dose proportionality. Serial blood samples were collected and analyzed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Since S002-333 is a racemate consisting of S004-1032 (R) and S007-1558 (S), same samples were analyzed using a chiralcel column so as to evaluate the respective enantiomers.

3.?The peak plasma concentration, after oral administration, occurred at ～10?h post-dose. The clearance (CL) and volume of distribution (V_d) after i.v. dose were found to be 3.05?±?0.09?l/h/kg and 6.73?±?1.16?l/kg, respectively. The absolute oral bioavailability of S002-333 was 16.32%, whereas it was 6.62 and 5.90% for R- and S-enantiomers, respectively. The absolute bioavailability of 10, 20 and 40?mg/kg doses were found to be 27.91, 14.39 and 16.91%, respectively. The PAMPA (parallel artificial membrane permeability assay) assay shows that S002-333 has a low-passive permeability at gastric and intestinal environment.

4.?In conclusion, S002-333 has low-passive permeability, low CL and large V_d. The R-enantiomer has a “slightly” greater bioavailability than the S-enantiomer.     

Absorption,metabolism and excretion of [14C]gemigliptin,a novel dipeptidyl peptidase 4 inhibitor,in humans

Abstract

1. Gemigliptin (formerly known as LC15-0444) is a newly developed dipeptidyl peptidase 4 inhibitor for the treatment of type 2 diabetes. Following oral administration of 50?mg (5.4?MBq) [¹⁴C]gemigliptin to healthy male subjects, absorption, metabolism and excretion were investigated.

2. A total of 90.5% of administered dose was recovered over 192?hr postdose, with 63.4% from urine and 27.1% from feces. Based on urinary recovery of radioactivity, a minimum 63.4% absorption from gastrointestinal tract could be confirmed.

3. Twenty-three metabolites were identified in plasma, urine and feces. In plasma, gemigliptin was the most abundant component accounting for 67.2%?～?100% of plasma radioactivity. LC15-0636, a hydroxylated metabolite of gemigliptin, was the only human metabolite with systemic exposure more than 10% of total drug-related exposure. Unchanged gemigliptin accounted for 44.8%?～?67.2% of urinary radioactivity and 27.7%?～?51.8% of fecal radioactivity. The elimination of gemigliptin was balanced between metabolism and excretion through urine and feces. CYP3A4 was identified as the dominant CYP isozyme converting gemigliptin to LC15-0636 in recombinant CYP/FMO enzymes.     

Dose-Dependent Pharmacokinetics of MK-417, a Potent Carbonic Anhydrase Inhibitor,in Experimental Polycythemic and Anemic Rats

MK-417 is a potent carbonic anhydrase inhibitor currently under clinical investigation as a topical ocular hypotensive agent. While present in most of the tissues, carbonic anhydrase predominates in red blood cells. Earlier studies from our laboratory have demonstrated that carbonic anhydrase plays an important role in the elimination kinetics of MK-417 and that the enzyme can be saturated when MK-417 exceeds the stoichiometric concentration of the enzyme. Since carbonic anhydrase is an intracellular enzyme in erythrocytes, conditions which may change the hematocrit can alter the load of MK-417 needed to saturate carbonic anhydrase. It is, therefore, important to determine the effects of anemic and polycythemic states on the pharmacokinetics of MK-417. The anemic state in rats was obtained by replacing whole blood with donor plasma (12–15 ml), while polycythemia was induced by infusion of 12 to 15 ml of whole blood. At low doses (0.05 and 0.1 mg/kg), the pharmacokinetic parameters for MK-417 remained unchanged and there were no significant differences in the pharmacokinetic parameters among the anemic, polycythemic, and normal rats. The total blood clearance and apparent volume of distribution were increased markedly when the dose exceeded 0.2 mg/kg in anemic rats and 0.5 and 1 mg/kg in normal and polycythemic rats, respectively. Clearly, the dose of MK-417 required to saturate the enzyme was different among the three groups of animals. However, the terminal half-life was dose independent and not influenced by hematocrit. At high doses (1 and 2 mg/kg), significant differences in total blood clearance and apparent volume of distribution were observed in the three groups of rats with the following rank: anemic rats > normal rats > polycythemic rats. There was a strong inverse correlation between total blood clearance and hematocrit and between apparent volume of distribution and hematocrit.     

Pharmacokinetics of Zopolrestat,a Carboxylic Acid Aldose Reductase Inhibitor,in Normal and Diabetic Rats

The pharmacokinetics of zopolrestat, a carboxylic acid aldose reductase inhibitor, were examined in normal male rats dosed intravenously at 2 mg/kg and in normal and streptozotocin-diabetic male rats after oral administration at 50 mg/kg. After oral dosing, C _max was 127 µg/ml for normal rats and 144 µg/ml for diabetic rats. AUC(0–), however, was lower for diabetic rats than for normal rats and plasma half-life was longer in normal rats (8.0 vs 6.6 hr). Half-lives of zopolrestat in nerve, kidney, and lens were longer than plasma half-life and were similar for both diabetic and normal rats. Less than 2% of the dose was excreted in the urine as unchanged zopolrestat during the 48-hr period following dosing by diabetic or normal rats. Protein binding of zopolrestat was less extensive in plasma from diabetic rats than in plasma from normal rats. Similar kinetics were observed in diabetic animals receiving-five daily doses of zopolrestat at 50 mg/kg/day. There was no plasma or liver accumulation of zopolrestat at steady state, consistent with the observed half-lives. However, zopolrestat did accumulate in nerve, kidney, and lens to varying degrees during multiple dosing, reflecting the longer half-lives of zopolrestat in these tissues.     

Pharmacokinetics,mass balance,and metabolism of [14C]vicagrel,a novel irreversible P2Y12 inhibitor in humans

Vicagrel, a novel irreversible P2Y₁₂ receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [¹⁴C]vicagrel (120 µCi). Vicagrel absorption was fast (T_max = 0.625 h), and the mean t_1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUC_inf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC_0–8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.     

Evaluation of Prediction Accuracy for Volume of Distribution in Rat and Human Using In Vitro,In Vivo,PBPK and QSAR Methods

Volume of distribution at steady state (V_ss) is an important pharmacokinetic parameter of a drug candidate. In this study, V_ss prediction accuracy was evaluated by using: (1) seven methods for rat with 56 compounds, (2) four methods for human with 1276 compounds, and (3) four in vivo methods and three Kp (partition coefficient) scalar methods from scaling of three preclinical species with 125 compounds. The results showed that the global QSAR models outperformed the PBPK methods. Tissue fraction unbound (f_u,t) method with adipose and muscle also provided high V_ss prediction accuracy. Overall, the high performing methods for human V_ss prediction are the global QSAR models, Øie-Tozer and equivalency methods from scaling of preclinical species, as well as PBPK methods with Kp scalar from preclinical species. Certain input parameter ranges rendered PBPK models inaccurate due to mass balance issues. These were addressed using appropriate theoretical limit checks. Prediction accuracy of tissue Kp were also examined. The f_u,t method predicted Kp values more accurately than the PBPK methods for adipose, heart and muscle. All the methods overpredicted brain Kp and underpredicted liver Kp due to transporter effects. Successful V_ss prediction involves strategic integration of in silico, in vitro and in vivo approaches.