Metabolism of deltamethrin and cis- and trans-permethrin by rat and human liver microsomes,liver cytosol and plasma preparations

1. The metabolism of deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in liver microsomes, liver cytosol and plasma from male Sprague–Dawley rats aged 15, 21 and 90 days and from adult humans.

2. DLM and CPM were metabolised by rat hepatic microsomal cytochrome P450 (CYP) enzymes and to a lesser extent by microsomal and cytosolic carboxylesterase (CES) enzymes, whereas TPM was metabolised to a greater extent by CES enzymes.

3. In human liver, DLM and TPM were mainly metabolised by CES enzymes, whereas CPM was metabolised by CYP and CES enzymes.

4. The metabolism of pyrethroids by cytosolic CES enzymes contributes to the overall hepatic clearance of these compounds.

5. DLM, CPM and TPM were metabolised by rat, but not human, plasma CES enzymes.

6. This study demonstrates that the ability of male rats to metabolise DLM, CPM and TPM by hepatic CYP and CES enzymes and plasma CES enzymes increases with age. In all instances, apparent intrinsic clearance values were lower in 15 than in 90?day old rats. As pyrethroid-induced neurotoxicity is due to the parent compound, these results suggest that DLM, CPM and TPM may be more neurotoxic to juvenile than to adult rats.

     

Disposition and metabolism of the G protein-coupled receptor 40 agonist TAK-875 (fasiglifam) in rats,dogs, and humans

1. The absorption, distribution, metabolism, and excretion of fasiglifam were investigated in rats, dogs, and humans.

2. The absolute oral bioavailability of fasiglifam was high in all species (>76.0%).

3. After oral administration of [¹⁴C]fasiglifam, the administered radioactivity was quantitatively recovered and the major route of excretion of radioactivity was via feces in all species.

4. Fasiglifam was a major component in the plasma and feces in all species. Its oxidative metabolite (M-I) was observed as a minor metabolite in rat and human plasma (<10% of plasma radioactivity). In human plasma, hydroxylated fasiglifam (T-1676427), the glucuronide of fasiglifam (fasiglifam-G), and the glucuronide of M-I were detected as additional minor metabolites (<2% of plasma radioactivity). None of these metabolites were specific to humans. Fasiglifam-G was the major component in the rat and dog bile.

5. In vitro cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) reaction phenotyping indicated that oxidation (to form M-I and T-1676427) and glucuronidation of fasiglifam are mainly mediated by CYP3A4/5 and UGT1A3, respectively.

6. Fasiglifam and fasiglifam-G are substrates of BCRP and Mrp2/MRP2, respectively.

7. Glucuronidation of fasiglifam-G was found to be the predominant elimination pathway of fasiglifam in all species tested, including humans.

     

Metabolism and disposition of lesinurad,a uric acid reabsorption inhibitor,in humans

1. The objectives of this study were to determine the absolute bioavailability of lesinurad and to characterized its disposition in humans.

2. The oral bioavailability assessment was performed using a clinical design of simultaneous dosing of a therapeutic oral dose of lesinurad with an intravenous infusion of [¹⁴C]lesinurad microdose. The bioavailability of lesinurad was determined to be 100%.

3. The disposition of lesinurad in humans involves hepatic oxidation and renal elimination following administration of oral [¹⁴C]lesinurad dose.

4. Metabolism of lesinurad occurred post-systemically with low circulating levels of metabolites <3% of total radioactivity as 74.2% of total radioactivity was attributed to lesinurad.

5. In vitro metabolism studies identified CYP2C9 as the predominant isoform, and summation of metabolites indicated that it was responsible for ～50% of metabolism.

     

Investigation of disposition for TAK-448, a synthetic peptide of kisspeptin analog,in rats and dogs using the radiolabeled TAK-448 suitable for pharmacokinetic study

1. Disposition of 2-(N-acetyl-d-tyrosyl-trans-4-hydroxy-l-prolyl-l-asparaginyl-l-threonyl-l-phenylalanyl) hydrazinocarbonyl-L-leucyl-N^ω-methyl-l-arginyl-l-tryptophanamide monoacetate (TAK-448, RVT-602), a synthetic kisspeptin analog, was investigated after parenteral dosing of radiolabeled TAK-448 ([d-Tyr-¹⁴C]TAK-448) to rats and dogs, and it was confirmed if the radiolabeling position at d-Tyr was eligible for assessment of in vivo disposition.

2. Dosed radioactivity was rapidly and well absorbed after subcutaneous administration and an appreciable amount of unchanged TAK-448 (TAK-448F) and a hydrolyzed metabolite, M-I, were detected in the plasma of rats and dogs.

3. After intravenous administration of [d-Tyr-¹⁴C]TAK-448 to rats, the radioactivity widely distributed to tissues with relatively higher concentrations in kidney and urinary bladder.

4. The radioactivity was decreased rapidly from the tissues.

5. After subcutaneous administration of [d-Tyr-¹⁴C]TAK-448 to rats and dogs, the dosed radioactivity was almost completely recovered by 48 and 72?h in rats and dogs, respectively, and most of the radioactivity was excreted in urine after extensive metabolism in the two species.

6. These results suggest that TAK-448 has an acceptable pharmacokinetic profile for clinical evaluation and development, and demonstrate that the synthesized [D-Tyr-¹⁴C]TAK-448 used in this study represents a favorable labeling position to evaluate disposition properties of this compound.

     

Disposition of tris(4-chlorophenyl)methanol and tris(4-chlorophenyl)methane in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following oral and intravenous administration

1. Tris(4-chlorophenyl)methane (TCPME) and tris(4-chlorophenyl)methanol (TCPMOH) have been detected in various biota and human tissues.

2. The current studies were undertaken to investigate the disposition and metabolism of TCPME and TCPMOH in rats and mice.

3. [¹⁴C]TCPME was well absorbed (≥66%) in male rats and mice following a single oral administration of 1, 10, or 100?mg/kg. The excretion of [¹⁴C]TCPME-derived radioactivity in urine (≤2.5%) and feces (≤18%) was low. The administered dose was retained in tissues (≥?64%) with adipose containing the highest concentrations. The metabolism of TCPME was minimal. The disposition and metabolism of [¹⁴C]TCPME in females was similar to males.

4. The time to reach maximum concentration was ≤7?h, the plasma elimination half-life was ≥31?h, and the bioavailability was ≥82% following a 10?mg/kg oral dose of [¹⁴C]TCPME in male rats and mice.

5. The disposition of [¹⁴C]TCPMOH was similar to that of [¹⁴C]TCPME.

6. Following an intravenous administration of [¹⁴C]TCPME or [¹⁴C]TCPMOH in male rats and mice, the pattern of disposition was similar to that of oral administration.

7. In conclusion, both TCPME and TCPMOH are readily absorbed and highly bioavailable following a single oral administration pointing to importance of assessing the toxicity of these chemicals.

     

The effect of elevated α1-acid glycoprotein on the pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor,in rats

1. The pharmacokinetics of TAK-272 (SCO-272), an orally active renin inhibitor, was investigated in rats with subcutaneously injected turpentine oil, which was an inflammation animal model.

2. Following intravenous administration of TAK-272 to the turpentine-treated rats, the systemic clearance and volume of distribution decreased with the elevated plasma α₁-acid glycoprotein (AGP) levels. The elevated plasma AGP levels were negatively correlated with the plasma unbound fraction of TAK-272 in the rats. Although the AUCs of total TAK-272 in the turpentine-treated rats were higher than those in the control rats after intravenous and oral administration, those of unbound TAK-272, which seem to directly contribute to the pharmacological effect and safety, were nearly equal between the turpentine-treated and control rats in the respective dose routes. TAK-272 has been shown to primarily bind to AGP in the human plasma.

3. These results strongly suggested that the pharmacokinetic of TAK-272 in humans would also be affected by the variation in the plasma AGP levels and should be discussed with not only the total concentrations but also the unbound concentrations in the clinical trial for patients with elevated plasma AGP levels.

     

Preclinical assessment of the ADME,efficacy and drug-drug interaction potential of a novel NAMPT inhibitor

1. GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers.

2. Plasma clearance was low in monkeys and dogs (9.14?mL min^?1?kg^?1 and 4.62?mL min^?1?kg^?1, respectively) and moderate in mice and rats (36.4?mL min^?1?kg^?1 and 19.3?mL min^?1?kg^?1, respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively.

3. Allometric scaling predicted a low clearance of 3.3?mL min^?1?kg^?1 and a volume of distribution of 1.3?L kg^?1 in human.

4. Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15?mg/kg BID (AUC?=?10.4?µM h).

5. Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP.

6. Simcyp^® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low.

7. Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.

     

In vivo multiple metabolic pathways for a novel G protein-coupled receptor 119 agonist DS-8500a in rats: involvement of the 1,2,4-oxadiazole ring-opening reductive reaction in livers under anaerobic conditions

1. A 1,2,4-oxadiazole ring-containing compound DS-8500a was developed as a novel G protein-coupled receptor 119 agonist. In vivo metabolic fates of [¹⁴C]DS-8500a differently radiolabeled in the benzene ring or benzamide side carbon in rats were investigated.

2. Differences in mass balances were observed, primarily because after the oxadiazole ring-opening and subsequent ring-cleavage small-molecule metabolites containing the benzene side were excreted in the urine, while those containing the benzamide side were excreted in the bile.

3. DS-8500a was detected at trace levels in urine and bile, demonstrating extensive metabolism prior to urinary/biliary excretion. At least 16 metabolite structures were proposed in plasma, urine, and bile samples from rats treated with [¹⁴C]DS-8500a.

4. Formation of a ring-opened metabolite (reduced DS-8500a) in hepatocytes of humans, monkeys, and rats was confirmed; however, it was not affected by typical inhibitors of cytochrome P450s, aldehyde oxidases, or carboxylesterases in human hepatocytes. Extensive formation of the ring-opened metabolite was observed in human liver microsomes fortified with an NADPH-generating system under anaerobic conditions.

5. These results suggest an in vivo unique reductive metabolism of DS-8500a is mediated by human non-cytochrome P450 enzymes.

     

Absorption,disposition, metabolism and excretion of [14C]mizagliflozin,a novel selective SGLT1 inhibitor,in rats

1. The pharmacokinetic and metabolite profiles of mizagliflozin, a novel selective sodium glucose co-transporter 1 inhibitor designed to act only in the intestine, were investigated in rats.

2. Mizagliflozin administrated intravenously (0.3?mg/kg) and orally (3?mg/kg) declined with a short half-life (0.23 and 1.14?h, respectively). The absolute bioavailability was only 0.02%. Following intravenous administration of [^14?C]mizagliflozin (0.3?mg/kg), radioactivity in plasma was also rapidly declined. Up to 24?h after oral administration of [^14?C]mizagliflozin (1?mg/kg), radioactivity was recovered in the faeces (98.4%) and in the urine (0.8%). No remarkable accumulation of radioactivity in tissues was observed using tissue dissection technique and whole body autoradiography.

3. Orally dosed [^14?C]mizagliflozin was mostly metabolised to its aglycone, KP232, in the intestine. In the plasma, KP232 and its glucuronide were predominant. KP232 glucuronide was also prominent in the bile and was recovered as KP232 in the faeces possibly because of the deconjugation by gut microflora. Mizagliflozin was observed neither in the urine nor the faeces.

4. These findings suggest that orally administered mizagliflozin is poorly absorbed, contributing to low systemic exposure; if absorbed, mizagliflozin is rapidly cleared from circulation.

     

Disposition and metabolism of [14C]lemborexant,a novel dual orexin receptor antagonist,in rats and monkeys

1. The disposition and metabolism of lemborexant, a novel dual orexin receptor antagonist currently under development as a therapeutic agent for insomnia disorder, were evaluated after a single oral administration of [¹⁴C]lemborexant in Sprague-Dawley rats (10?mg/kg) and cynomolgus monkeys (3?mg/kg).

2. In both species, [¹⁴C]lemborexant was rapidly absorbed: radioactivity concentration in blood peaked at 0.83–1.8?h, and decreased with elimination half-life of 110?h. The radioactivity administered was excreted primarily into faeces, with relatively little excreted into urine.

3. Lemborexant was not detected in bile, urine or faeces, indicating that lemborexant administered orally was completely absorbed from the gastrointestinal tract and that the main elimination pathway was metabolism in both species.

4. In rats, lemborexant was found to be minor in plasma (≤5.2% of total radioactivity), and M9 (hydroxylated form) was the major circulating metabolite. In monkeys, the major circulating components were lemborexant, M4 (N-oxide metabolite), M13 (di-oxidised form), M14 (di-oxidised form) and M16 (glucuronide of mono-oxidised form).

5. In both species, lemborexant was metabolised to various metabolites by multiple pathways, the primary of which was oxidation of the dimethylpyrimidine or fluorophenyl moiety.

     

Distribution and metabolism of 14C-sulfoquinovosylacylpropanediol (14C-SQAP) after a single intravenous administration in tumor-bearing mice

1. Sulfoquinovosylacylpropanediol (SQAP) is a novel potent radiosensitizer that inhibits angiogenesis in vivo and results in increased oxigenation and reduced tumor volume. We investigated the distribution, metabolism, and excretion of SQAP in male KSN-nude mice transplanted with a human pulmonary carcinoma, Lu65.

2. For the metabolism analysis, a 2?mg (2.98?MBq)/kg of [glucose-U-¹⁴C]-SQAP (CP-3839) was intravenously injected. The injected SQAP was decomposed into a stearic acid and a sulfoquinovosylpropanediol (SQP) in the body.

3. The degradation was relatively slow in the carcinoma tissue.1,3-propanediol[1-¹⁴C]-SQAP (CP-3635) was administered through intravenous injection of a 1?mg (3.48?MBq)/kg dose followed by whole body autoradiography of the mice.

4. The autoradiography analysis demonstrated that SQAP rapidly distributed throughout the whole body and then quickly decreased within 4 hours except the tumor and excretion organs such as liver, kidney.

5. Retention of SQAP was longer in tumor parts than in other tissues, as indicated by higher levels of radioactivity at 4 hours. The radioactivity around the tumor had also completely disappeared within 72 hours.

     

In vitro stability and metabolism of O2′, O3′, O5′-tri-acetyl-N6-(3-hydroxylaniline) adenosine in rat,dog and human plasma: Chemical hydrolysis and role of plasma esterases

1. O2′, O3′, O5′-tri-acetyl-N⁶-(3-hydroxylaniline)adenosine (WS070117), a new structure-type lipid regulator, is being developed in pre-clinical study. In order to monitor drug kinetics it is essential to understand pre-analytical factors that may affect drug assay.

2. In vitro stability and metabolism were investigated using high-performance liquid chromatography (HPLC) method in this study. The hydrolysis products were identified by HPLC–mass spectrometry (MS)/MS method. The esterases involved in WS070117 hydrolysis was assigned via inhibition rate assay.

3. It was found that WS070117 was chemically unstable in alkaline solutions compared to acidic and near neutral solutions. Enzymatic hydrolysis was even more rapid. Hydrolytic rate constants differ between species, being 4.24, 5.96?×?10^?3 and 6.85?×?10^?2 min^?1 in rat, dog and human plasma at 37°C, respectively. The hydrolysis was catalyzed by plasma esterase because NaF (sodium fluoride: a general esterase inhibitor) inhibited WS070117 hydrolysis and metabolite production. Hydrolysis was fast in rat plasma and was catalysed by carboxylesterase and butyrylcholinesterase. In dog plasma, carboxylesterase, butyrylcholinesterase and paraoxonase were mainly responsible. Butyrylcholinesterase was the major esterase involved in WS070117 hydrolysis in human plasma. The WS070117 hydrolysis in plasma proceeded by gradual loss of acetyl groups.

4. The knowledge of in vitro drug stability and metabolic pathways identified in this study will be essential for future pre-clinical and clinical pharmacokinetics studies.

     

Effect of pretreatment regimens of 1-aminobenzotriazole on metabolism and gastric emptying of probe compounds in rat

1. 1-Aminobenzotriazole (ABT) is a mechanism-based inactivator of major cytochrome P450 (CYP) enzymes, which is used in multiple mechanistic studies.

2. The purpose was to evaluate the effect of 2 and 16-h pretreatment regimens of ABT on the exposures of triazolam in rat. Another objective was to evaluate the effect of ABT on gastric emptying of acetaminophen.

3. Plasma area under the curve (AUC) of triazolam was increased by 101-fold and 81-fold for the rats pretreated with ABT at 2 and 16?h, respectively, compared to control rats. Time to reach maximum concentration was 0.3, 4.8 and 3.7?h in control, 2 and 16-h pretreatment animals, respectively. In the case of acetaminophen, where T_max was not delayed, the mean absorption time (MAT) in control, 2 and 16?h ABT pretreatment groups were 0.3, 4.6 and 2.9?h, respectively, suggesting delayed absorption. This hypothesis was further supported by GastroPlus^TM simulation.

4. In summary, extent of triazolam absorption was increased to a similar extent with both 2 and 16?h ABT pretreatment regimens, suggesting that either of the regimen can be used to increase parent exposures in rat. With ABT pretreatment, delayed absorption of triazolam and acetaminophen was observed, as suggested by delay in T_max and MAT, respectively.

     

Human urinary concentrations of monoisononyl phthalate estimated using physiologically based pharmacokinetic modeling and experimental pharmacokinetics in humanized-liver mice orally administered with diisononyl phthalate

1. Diisononyl phthalate (DINP) used as a plasticizer is a mixture of compounds consisting of isononyl esters of phthalic acid. There are concerns about the bioaccumulation of such esters in humans. A [phenyl-U-¹⁴C]DINP mixture was synthesized and orally administered (50?mg/kg body weight) to control and humanized-liver mice and their pharmacokinetics were determined.

2. Monoisononyl phthalate (MINP, a primary metabolite of DINP), oxidized MINP (isomers with hydroxy, carbonyl, and carboxy functional groups), and their glucuronides were detected in plasma from control and humanized-liver mice. Biphasic plasma concentration–time curves of MINP and its glucuronide were seen in control mice. In contrast, no such biphasic relationship was seen in humanized-liver mice, in which MINP and oxidized MINP were extensively excreted in the urine within 48?h.

3. Animal biomonitoring equivalents of MINP and oxidized MINP from humanized-liver mice studies were scaled to human equivalents using known species allometric scaling factors with a simple physiologically based pharmacokinetic (PBPK) model.

4. Estimated urinary oxidized MINP concentrations in humans were roughly consistent with reported concentrations of MINP (with a different side chain). The simplified PBPK model could estimate human urinary concentrations of MINP after ingestion of DINP and was capable of both forward and reverse dosimetry.

     

Metabolism of deltamethrin and cis- and trans-permethrin by human expressed cytochrome P450 and carboxylesterase enzymes

1. The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes.

2. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CL_int) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5. None of the pyrethroids were metabolised by CYP2A6, CYP2E1, CYP3A7 or CYP4A11.

3. DLM, CPM and TPM were metabolised by both human CES1 and CES2 enzymes.

4. Apparent CL_int values for pyrethroid metabolism by CYP and CES enzymes were scaled to per gram of adult human liver using abundance values for microsomal CYP enzymes and for CES enzymes in liver microsomes and cytosol. TPM had the highest and CPM the lowest apparent CL_int values for total metabolism (CYP and CES enzymes) per gram of adult human liver.

5. Due to their higher abundance, all three pyrethroids were extensively metabolised by CES enzymes in adult human liver, with CYP enzymes only accounting for 2%, 10% and 1% of total metabolism for DLM, CPM and TPM, respectively.

     

Pharmacokinetics of anticoagulants apixaban,dabigatran, edoxaban and rivaroxaban in elderly Japanese patients with atrial fibrillation treated in one general hospital

1. Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76?years) treated with apixaban (2.5 or 5.0?mg twice daily), dabigatran etexilate (110 or 150?mg twice daily), edoxaban (30 or 60?mg once daily) or rivaroxaban (10 or 15?mg once daily) at one general hospital.

2. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose.

3. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban.

4. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.

     

Physiologically-based pharmacokinetic modeling for mirabegron: a multi-elimination pathway mediated by cytochrome P450 3A4, uridine 5'-diphosphate-glucuronosyltransferase 2B7, and butyrylcholinesterase

1. This was the first study to construct a physiologically-based pharmacokinetic (PBPK) model for mirabegron which incorporates the overall elimination pathways of metabolism by cytochrome P450 (CYP) 3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7, and butyrylcholinesterase (BChE) and renal excretion. The objective was to assess the risk of drug-drug interactions (DDIs) by estimating the contribution of each elimination pathway and simulating the magnitude of the DDIs with UGT2B7 inhibitors.

2. A PBPK model for mirabegron was constructed to reproduce the plasma concentration-time curves from a phase 1 study and the magnitude of the DDI with ketoconazole taking into account the overall elimination pathways. The PBPK model was subsequently verified using data from other DDI studies.

3. The constructed PBPK model estimated the contribution for each elimination pathway: 44% and 29% for CYP3A4 and UGT2B7 in the liver, 1.6% for UGT2B7 in the kidney, 3.2% for BChE in plasma, and 22% for renal excretion.

4. Co-administration of probenecid (an UGT2B7 inhibitor) or fluconazole (an UGT2B7 and CYP3A4 inhibitor) was predicted to increase area under the curve for mirabegron to 115% or 174%, respectively.

5. In conclusion, PBPK modeling and simulation revealed a low DDI risk for mirabegron following co-administration with BChE or UGT2B7 inhibitors.

     

Pharmacokinetic modeling and simulation of etodolac following single oral administration in dogs

1. Etodolac is a nonsteroidal anti-inflammatory drug with selective cyclooxygenase-2 inhibition to treat pain and inflammation associated with osteoarthritis in humans and dogs. The aim of the study was to investigate the pharmacokinetics of etodolac following single oral administration of 200?mg to 10 healthy beagle dogs.

2. The plasma concentrations of etodolac were detected using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was conducted using the noncompartmental method and modeling approaches.

3. Etodolac was rapidly absorbed (T_max?=?0.85?h, K_a?=?1.49?h^?1) and slowly eliminated (T_1/2?=?39.55?h) following oral administration to the dogs. A two-compartment pharmacokinetic model with first-order absorption and elimination rate constants was successfully explained for the pharmacokinetic aspects of etodolac in dogs. From a Monte Carlo simulation (1000 repetitions), the accumulation index and AUC_τ at steady state were predicted as 1.60 [90% confidence intervals (CI), 1.24–2.81] and 408.18?ng·hr/mL [90% CI, 271.26–590.58?ng·hr/mL], respectively.

4. This study will help to enact a more accurate optimal dosing regimen of etodolac in dogs with osteoarthritis, and may be useful in developing a novel formulation of etodolac for human in the future.

     

QSPR modelling of in vitro degradation half-life of acyl glucuronides

1. Acyl glucuronidation is an important Phase II biotransformation, which is an efficient detoxification mechanism for the metabolism of carboxylic acid group-containing drugs. However, the reactivity of acyl glucuronide (AG) metabolites associated with short half-lives may be an indication of idiosyncratic drug toxicity.

2. The degradation half-lives of AGs elucidate several important reactions such as hydrolysis, acyl migration and covalent binding to proteins. Prediction of degradation half-life using computational methods is a promising alternative approach to costly and time-consuming experiments, enabling a priori evaluation of the properties of drug candidates during the drug design process.

3. The main objective of the present study was to develop a linear model for the quantitative prediction of half-lives of acyl glucuronidated drug-like compounds. The proposed model revealed that the number of total quaternary carbons, the complexity of the ring in the compound, Sanderson electronegativities, and dipole moment of the compound are important molecular features in predicting the half-life of an AG.

4. The rigorously validated model can contribute to a better understanding of molecular features of these drugs to predict degradation half-lives.

     

Comparison of the hepatic and thyroid gland effects of sodium phenobarbital and pregnenolone-16α-carbonitrile in wild-type and constitutive androstane receptor (CAR)/pregnane X receptor (PXR) knockout rats

1. The hepatic and thyroid gland effects of the constitutive androstane receptor (CAR) activator sodium phenobarbital (NaPB) and the pregnane X receptor (PXR) activator pregnenolone-16α-carbonitrile (PCN) were examined in male Sprague-Dawley wild-type (WT) and knockout (KO) rats lacking both hepatic CAR and PXR receptors (CAR KO/PXR KO rats).

2. The treatment of WT rats for 7?d with 500?ppm NaPB in the diet and 100?mg/kg/d PCN by gavage resulted in increased relative liver weight, hepatocyte hypertrophy, increased hepatocyte replicative DNA synthesis (RDS) and induction of cytochrome P450 CYP2B and CYP3A subfamily enzymes. NaPB and PCN also induced thyroid gland follicular cell RDS and hepatic microsomal UDP-glucuronosyltransferase activity towards thyroxine as substrate. These effects were not observed in the liver and thyroid gland of CAR KO/PXR KO rats.

3. Male C57BL/6?J (WT) and CAR KO/PXR KO mice were given 1000?ppm NaPB in the diet for 7?d. In WT, but not in CAR KO/PXR KO, mice NaPB treatment resulted in liver hypertrophy and induction of hepatocyte RDS and Cyp2b enzymes.

4. These results suggest that the CAR KO/PXR KO rat and mouse models are useful experimental models for mode of action studies with rodent CAR activators.