The pharmacokinetics and disposition of GDC-0879, a small molecule B-RAF kinase inhibitor, was characterized in mouse, rat, dog, and monkey.
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.
Plasma protein binding of GDC-0879 in mouse, rat, dog, monkey, and humans ranged from 68.8% to 81.9%.
In dog, the major ketone metabolite (G-030748) of GDC-0879 appeared to be formation rate-limited.
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.
5-{2-[4-(3,4-Difluorophenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoic acid (1) is a novel, potent, and selective agonist of the peroxisome proliferator-activated receptor alpha (PPAR-α).
In preclinical species, compound 1 demonstrated generally favourable pharmacokinetic properties. Systemic plasma clearance (CLp) after intravenous administration was low in Sprague–Dawley rats (3.2?±?1.4?ml min?1 kg?1) and cynomolgus monkeys (6.1?±?1.6?ml min?1 kg?1) resulting in plasma half-lives of 7.1?±?0.7?h and 9.4?±?0.8?h, respectively. Moderate bioavailability in rats (64%) and monkeys (55%) was observed after oral dosing. In rats, oral pharmacokinetics were dose-dependent over the dose range examined (10 and 50?mg kg?1).
In vitro metabolism studies on 1 in cryopreserved rat, monkey, and human hepatocytes revealed that 1 was metabolized via oxidation and phase II glucuronidation pathways. In rats, a percentage of the dose (approximately 19%) was eliminated via biliary excretion in the unchanged form.
Studies using recombinant human CYP isozymes established that the rate-limiting step in the oxidative metabolism of 1 to the major primary alcohol metabolite M1 was catalysed by CYP3A4.
Compound 1 was greater than 99% bound to plasma proteins in rat, monkey, mouse, and human.
No competitive inhibition of the five major cytochrome P450 enzymes, namely CYP1A2, P4502C9, P4502C19, P4502D6 and P4503A4 (IC50’s?>?30 μM) was discerned with 1.
Because of insignificant turnover of 1 in human liver microsomes and hepatocytes, human clearance was predicted using rat single-species allometric scaling from in vivo data. The steady-state volume was also scaled from rat volume after normalization for protein-binding differences. As such, these estimates were used to predict an efficacious human dose required for 30% lowering of triglycerides.
In order to aid human dose projections, pharmacokinetic/pharmacodynamic relationships for triglyceride lowering by 1 were first established in mice, which allowed an insight into the efficacious concentrations required for maximal triglyceride lowering. Assuming that the pharmacology translated in a quantitative fashion from mouse to human, dose projections were made for humans using mouse pharmacodynamic parameters and the predicted human pharmacokinetic estimates.
First-in-human clinical studies on 1 following oral administration suggested that the human pharmacokinetics/dose predictions were in the range that yielded a favourable pharmacodynamic response.
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?μM. Ki’s estimated for P4502C8, P4502C9 and P4502C19 and were 6.0, 5.4 and 24?μM, respectively. An evaluation with Simcyp® suggests that GDC-0449 has a low potential of inhibiting P4502C8 and P4502C9. Furthermore, GDC-0449 (15?μM) 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.
As a novel hydrogen sulfide-modulated agent, S-propargyl-L-cysteine (SPRC) is proven to be a potent cardioprotective candidate. Bioavailability and pharmacokinetics of SPRC (20?mg/kg) in beagle dogs after oral and intravenous administrations were investigated in this study. Plasma concentrations of SPRC were measured by a LC-MS/MS method.
Intravenous administration of SPRC (single dose) to beagle dogs gave a mean plasma half-life of 14.7?h, mean clearance of 0.4?ml min?1 kg?1 and mean apparent volume of distribution of 0.56?L/kg. Single oral administration was completely, fast absorbed (Tmax= 0.33?±?0.20?h) with a mean absolute availability of 112% and mean plasma half-life of 16.5?h.
Multiple oral administration (once daily for 10 consecutive days) of SPRC to dogs resulted in steady state plasma drug concentration being reached after seven doses and didn’t cause obvious accumulation. No significant difference was found between the single and multiple pharmacokinetic parameters.
Domperidone was evaluated in direct and time-dependent cytochrome P450 (CYP) 3A inhibition assays in human liver microsomes with midazolam and testosterone as probe substrates.
Domperidone was found to be a modest mechanism-based inhibitor of human and rat CYP3A. For human CYP3A, the inactivation constant (KI) is 12 μM, and the maximum inactivation rate (kinact) is 0.037?min?1.
A rat interaction study was conducted between midazolam and either a single dose or five daily doses of domperidone. Although a single oral dose of 10?mg kg?1 domperidone did not affect the pharmacokinetics of 10?mg kg?1 oral midazolam, five daily oral doses of domperidone almost doubled the area under the plasma concentration versus time curve (AUC) of midazolam, and increased the maximum plasma concentration (Cmax) of midazolam by 72%.
Based on the simulation and rat in vitro–in vivo extrapolation, it is predicted that co-administration of domperidone in humans could modestly increase (approximately 50%) the exposure of drugs that are primarily cleared by CYP3A.
Compound A [1-methyl-N-{(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxooctyl}piperidine-4-carboxamide is a potent class I histone deacetylase (HDAC) inhibitor that demonstrated good antiproliferative activity against human tumour cell lines of different origin.
This compound showed high in vivo clearance in rats (160?ml min?1 kg?1) due to metabolism. The main metabolite detected in urine after intravenous dosing was characterized as a dihydrohydroxy S-mercapturic acid conjugate. Following oral dosing, however, the mercapturic acid derivative was no longer the main metabolite but the major metabolites were mono- and di-glucuronide conjugates of oxidized species having a mass shift of +34 m/z with respect to the parent.
Comparison of plasma concentration after intra-arterial infusion and intravenous infusion and incubation with microsomes from different tissues (liver, kidney, small intestine and lung) in the presence of β-nicotinamide adenine dinucleotide phosphate (NADPH) indicated that the compound was highly cleared by the lung.
Oxidation of the naphthalene moiety was demonstrated to be the cause of the high in vivo clearance of compound A and the potential for bioactivation of this group was flagged.
The pharmacokinetics of lipoyl vildagliptin, a novel dipeptidyl peptidase IV (DPP IV) inhibitor, was studied in rats after oral administration for developing it as an antidiabetic agent.
A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method was developed to determine lipoyl vildagliptin in rat plasma. After an overnight fasting, rats were orally given lipoyl vildagliptin. Following a single oral dose of 25, 50, and 100?mg·kg?1, Tmax values were from 1.25 to 1.84?h, CL/F values were around 100?l h?1 kg?1. In the dose range, Cmax values (63.9–296?μg·l?1) and AUC0–∞values (260–1214?μg·h·l?1) were proportional to the doses.
In conclusion, this LC-MS/MS method for the determination of lipoyl vildagliptin in rat plasma was selective and sensitive. In rats, lipoyl vildagliptin displayed linear pharmacokinetics after a single oral dose in the range of 25–100?mg·kg?1. Lipoyl vildagliptin might have very high CL/F values and Vd/F values, which indicated that the bioavailability of this drug might be low or lipoyl vildagliptin might distribute extensively or accumulate in tissues in view of its high liposolubility.
The metabolism and excretion of a GABAA partial agonist developed for the treatment of anxiety, CP-409,092; 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide, were studied in rats following intravenous and oral administration of a single doses of [14C]CP-409,092.
The pharmacokinetics of CP-409,092 following single intravenous and oral doses of 4 and 15?mg kg?1, respectively, were characterized by high clearance of 169?±?18?ml min?1 kg?1, a volume of distribution of 8.99?±?1.46 l kg?1, and an oral bioavailability of 2.9% ± 3%.
Following oral administration of 100?mg kg?1 [14C]CP-409,092, the total recovery was 89.1% ± 3.2% for male rats and 89.3% ± 0.58% for female rats. Approximately 87% of the radioactivity recovered in urine and faeces were excreted in the first 48?h. A substantial portion of the radioactivity was measured in the faeces as unchanged drug, suggesting poor absorption and/or biliary excretion. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or faeces.
The major metabolic pathways of CP-409,092 were hydroxylation(s) at the oxo-tetrahydro-indole moiety and oxidative deamination to form an aldehyde intermediate and subsequent oxidation to form the benzoic acid. The minor metabolic pathways included N-demethylation and subsequent N-acetylation and oxidation.
The present work demonstrates that oxidative deamination at the benzylic amine of CP-409,092 and subsequent oxidation to form the acid metabolite seem to play an important role in the metabolism of the drug, and they contribute to its oral clearance and low exposure.
The aim was to identify the individual human cytochrome P450 (CYP) enzymes responsible for the in vitro N-demethylation of hydromorphone and to determine the potential effect of the inhibition of this metabolic pathway on the formation of other hydromorphone metabolites.
Hydromorphone was metabolized to norhydromorphone (apparent Km = 206?? 822?μM, Vmax = 104 ? 834?pmol?min?1?mg?1 protein) and dihydroisomorphine (apparent Km = 62 ? 557?μM, Vmax = 17 ? 122?pmol?min?1?mg?1 protein) by human liver microsomes.
In pooled human liver microsomes, troleandomycin, ketoconazole and sulfaphenazole reduced norhydromorphone formation by an average of 45, 50 and 25%, respectively, whereas furafylline, quinidine and omeprazole had no effect. In an individual liver microsome sample with a high CYP3A protein content, troleandomycin and ketoconazole inhibited norhydromorphone formation by 80%.
The reduction in norhydromorphone formation by troleandomycin and ketoconazole was accompanied by a stimulation in dihydroisomorphine production.
Recombinant CYP3A4, CYP3A5, CYP2C9 and CYP2D6, but not CYP1A2, catalysed norhydromorphone formation, whereas none of these enzymes was active in dihydroisomorphine formation.
In summary, CYP3A and, to a lesser extent, CYP2C9 catalysed hydromorphone N-demethylation in human liver microsomes. The inhibition of norhydromorphone formation by troleandomycin and ketoconazole resulted in a stimulation of microsomal dihydroisomorphine formation.
Intercellular adhesion molecule (ICAM)-1988 is a small molecule lymphocyte function-associated antigen-1 (LFA-1) antagonist being considered for its anti-inflammatory properties. Following intravenous administration of ICAM1988, clearances in mice, rats, dogs, and monkeys were 17.8, 3.31, 15.4, and 6.85 ml min?1 kg?1, respectively.
In mass balance studies using [14C]-ICAM1988 in rats dosed intravenously, unchanged ICAM1988 contributed to 25.1% of the dose.
In rats, the systemic bioavailability of ICAM1988 was improved to 0.28 when the drug was administered orally as its isobutyl ester, ICAM2660. In rats, this was consistent with the complete in vitro conversion of ICAM2660 to ICAM1988 in plasma, and liver and intestinal S9.
In dogs and monkeys, ICAM2660 did not improve the bioavailability of ICAM1988. This is consistent with limited in vitro conversion of ICAM2660 to ICAM1988 in plasma and liver S9.
In human in vitro studies, ICAM2660 conversion to ICAM1988 in liver was similar to rats while no conversion in plasma and intestinal S9 fractions were observed. Based on the in vitro metabolism similarities of human and rat, it would be anticipated that in human oral administration of ICAM2660 would improve the systemic exposure of ICAM1988.
Zinc acexamate (ZAC) is ionized to zinc and ?-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50?mg kg?1) and oral (100?mg kg?1) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50?mg kg?1) and oral (20, 50, and 100?mg kg?1) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20?mg kg?1 were evaluated in rats.
After oral administration of ZAC (20?mg kg?1), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats.
Affinity of rat tissues to zinc and AACA was low—the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10?µg ml?1—the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.
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.
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.
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.
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.
Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active metabolites is CYP mediated. This study compared the efficiency, in vivo, of the formation of prasugrel and clopidogrel thiolactones and their active metabolites.
The areas under the plasma concentration versus time curve (AUC) of the thiolactone intermediates in the portal vein plasma after an oral dose of prasugrel (1 mg kg?1) and clopidogrel (0.77 mg kg?1) were 15.8 ± 15.9 ng h ml?1 and 0.113 ± 0.226 ng h ml?1, respectively, in rats, and 454 ± 104 ng h ml?1 and 23.3 ± 4.3 ng h ml?1, respectively, in dogs, indicating efficient hydrolysis of prasugrel and little metabolism of clopidogrel to their thiolactones in the intestine.
The relative bioavailability of the active metabolites of prasugrel and clopidogrel calculated by the ratio of active metabolite AUC (prodrug oral administration/active metabolite intravenous administration) were 25% and 7%, respectively, in rats, and 25% and 10%, respectively, in dogs.
Single intraduodenal administration of prasugrel showed complete conversion of prasugrel, resulting in high concentrations of the thiolactone and active metabolite of prasugrel in rat portal vein plasma, which demonstrates that these products are generated in the intestine during the absorption process.
In conclusion, the extent of in vivo formation of the thiolactone and the active metabolite of prasugrel was greater than for clopidogrel’s thiolactone and active metabolite.
Mycophenolic acid (MPA), converted from the prodrug mycophenolate mofetil (MMF), is generated by intestinal and hepatic esterases. The role of carboxylesterase (CES) in MMF hydrolysis was examined in vitro using human liver microsomes. Vmax and Km values of MMF hydrolysis in pooled human liver microsomes were 1368?±?44 nmol min?1 mg?1 protein and 1030?±?65?μM, respectively.
Hydrolytic activity was inhibited by the CES inhibitors phenylmethylsulfonylfluoride, bis-p-nitorophenylphosphate and diisopropylfluorophosphate, with IC50 values of 77.1, 3.59 and 0.0312?μM, respectively.
Eighty Japanese renal transplant recipients that received repeated-doses of MMF, tacrolimus and prednisolone, were evaluated for MPA pharmacokinetics 28 days after transplantation to investigate the relationship between MPA pharmacokinetics and CES2 genetic polymorphisms.
No significant differences in MPA pharmacokinetics were observed between CES2 A4595G, C8721T or A-1548G genotype groups. CES2 allelic variants also did not appear to affect plasma MPA concentrations between individuals.
In conclusion, the study demonstrated that while CES1 and/or CES2 are involved in the hydrolysis of MMF to MPA, CES2 allelic variants appeared to make only a minor contribution to inter-personal differences in MPA pharmacokinetics.
We compared the intrinsic clearance (CLint) of a number of substrates in suspensions of fresh and cryopreserved human hepatocytes from seven donors.
CLint values for a cocktail incubation of phenacetin, diclofenac, diazepam, bufuralol, midazolam, and hydroxycoumarin were 4.9?±?3.4, 18?±?7.2, 5.1?±?4.9, 6.3?±?3.3, 9.8?±?5.8 and 22?±?14?μl min?1/106 cells, respectively, and they correlated well with corresponding CLint values using cryopreserved hepatocytes from 25 different donors.
CLint values of each cocktail substrate and 20 AstraZeneca new chemical entities were compared in fresh and cryopreserved hepatocytes from the same three donors. There was a statistically significant correlation between CLint in fresh and cryopreserved hepatocytes for each of the three livers (p?int values was 1.03.
In conclusion, the results add further support to the use of cryopreserved human hepatocytes as a screening model for the intrinsic clearance of new chemical entities.
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.
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.
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.
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).
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.
Simcyp® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low.
Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.
Valspodar is a P-glycoprotein inhibitor widely used in preclinical and clinical studies for overcoming multidrug resistance. Despite this, the pharmacokinetics of valspodar in rat, a commonly used animal model, have not been reported. Here, we report on the pharmacokinetics of valspodar in Sprague–Dawley rats following intravenous and oral administration of its Cremophor EL formulation, which has been used for humans in clinical trials.
After intravenous doses, valspodar displayed properties of slow clearance and a large volume of distribution. Its plasma unbound fraction was around 15% in the Cremophor EL formulation used in the study. After 10?mg kg?1 orally it was rapidly absorbed with an average maximal plasma concentration of 1.48?mg l?1 within approximately 2?h. The mean bioavailability of valspodar was 42.8%.
In rat, valspodar showed properties of low hepatic extraction and wide distribution, similar to that of its structural analogue cyclosporine A.
Levels of urinary dialkylphosphates (DAPs) are currently used as a biomarker of human exposure to organophosphorus insecticides (OPs). It is known that OPs degrade on food commodities to DAPs at levels that approach or exceed those of the parent OP. However, little has been reported on the extent of DAP absorption, distribution, metabolism and excretion.
The metabolic stability of O,O-dimethylphosphate (DMP) was assessed using pooled human and rat hepatic microsomes. Time-course samples were collected over 2?h and analyzed by LC-MS/MS. It was found that DMP was not metabolized by rat or pooled human hepatic microsomes.
Male Sprague–Dawley rats were administered DMP at 20?mg kg?1 via oral gavage and i.v. injection. Time-course plasma and urine samples were collected and analyzed by LC-MS/MS. DMP oral bioavailability was found to be 107?±?39% and the amount of orally administered dose recovered in the urine was 30?±?9.9% by 48?h.
The in vitro metabolic stability, high bioavailability and extent of DMP urinary excretion following oral exposure in a rat model suggests that measurement of DMP as a biomarker of OP exposure may lead to overestimation of human exposure.
Cytoprotective effects of liquiritigenin (LQ) against liver injuries have been reported, but its pharmacokinetics has not been studied in acute hepatitis. Thus, pharmacokinetics of LQ and its two conjugated glucuronide metabolites: 4′-O-glucuronide (M1) and 7-O-glucuronide (M2), in rats with acute hepatitis induced by d-galactosamine/lipopolysaccharide (GalN/LPS) rats or carbon tetrachloride-treated (CCl4-treated) rats were evaluated.
LQ was administered intravenously (20?mg kg?1) and orally (50?mg kg?1) to control GalN/LPS and CCl4-treated rats. Expression of uridine 5′-diphospho-glucuronosyltransferases 1A (UGT1A) and in vitro metabolism of LQ in hepatic and intestinal microsomes were also measured.
After intravenous administration of LQ, area under the plasma concentration-time curve (AUC) of LQ in GalN/LPS rats was significantly smaller than that in controls due to faster non-renal clearance, as a result of its greater free fraction in plasma and faster hepatic blood flow rate than the controls. In CCl4-treated rats, the AUCM1, 0?8 h/AUCLQ and AUCM2, 0?8 h/AUCLQ ratios were significantly greater than the controls due to decrease in biliary excretion of M1 and M2. However, no significant pharmacokinetic changes were observed in both acute hepatitis rats after oral administration due to comparable intestinal metabolism of LQ.
Modification of oral dosage regimen of LQ may not be necessary in patients with acute hepatitis; but human studies are required.
The elimination half-life of midazolam administered intravenously (5 mg kg?1) or orally (15 mg kg?1) was significantly decreased by 70% and 73%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg?1) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA.
The Cmax and area under the curve (AUC)0–∞ of midazolam were significantly (1.8–2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg?1). Thus, the oral bioavailability, estimated from the AUC0–∞, of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA.
Repeated administration of UDCA (300 mg kg?1 day?1) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver.
The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA.