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(R,R)-fenoterol (Fen), a β2-adrenoceptor agonist, is under clinical investigation in the treatment of congestive heart disease. The pharmacokinetics and metabolism of the 4-methoxyphenyl derivative of (R,R)-Fen, (R,R)-MFen, have been determined following intravenous and oral administration to the rat and compared with corresponding results obtained with (R,R)-Fen. Results from the study suggest that (R,R)-MFen can offer pharmacokinetic and metabolic advantages in comparison to an earlier (R,R)-Fen.
The oral administration revealed that the net exposure of (R,R)-MFen was about three-fold higher than that of (R,R)-Fen (7.2 versus 2.3?min × nmol ml?1), while intravenous administration proved that the clearance was significantly reduced, 48 versus 146?ml min?1 kg?1, the T1/2 was significantly longer, 152.9 versus 108.9?min, and the area under the curve (AUC) was significantly increased, 300 versus 119?min × nmol ml?1.
(R,R)-MFen was primarily cleared by glucuronidation associated with significant presystemic glucuronidation of the compound. After intravenous and oral administration of (R,R)-MFen, (R,R)-Fen and (R,R)-Fen-G were detected in the urine samples indicating that (R,R)-MFen was O-demethylated and subsequently conjugated to (R,R)-Fen-G. The total (R,R)-Fen and (R,R)-Fen-G as a percentage of the dose after intravenous administration was 3.6%, while after oral administration was 0.3%, indicating that only a small fraction of the drug escaped presystemic glucuronidation and was available for O-demethylation.
The glucuronidation pattern was confirmed by the results from in vitro studies where incubation of (R,R)-MFen with rat hepatocytes produced (R,R)-MFen-G, (R,R)-Fen and (R,R)-Fen-G, while incubation with rat intestinal microsomes only resulted in the formation of (R,R)-MFen-G.
We established a mechanism-based inhibition cocktail-substrate assay system using human liver microsomes and drug–probe substrates that enabled simultaneous estimation of the inactivation of main cytochrome P450 (CYP) enzymes, CYP2C9, CYP2D6, and CYP3A, in drug metabolism.
The inactivation kinetic parameters of typical mechanism-based inhibitors, tienilic acid, paroxetine, and erythromycin, for each enzyme in the cocktail-substrate assay were almost in agreement with the values obtained in the single-substrate assay.
Using this system, we confirmed that multiple CYP inactivation caused by mechanism-based inhibitors such as isoniazid and amiodarone could be detected simultaneously.
Mechanism-based inhibition potency can be estimated by the determination of the observed inactivation rate constants (kobs) at a single concentration of test compounds because the kobs of eleven CYP3A inactivators at 10?μM in the assay system nearly corresponded to kinact/KI values, an indicator of a compound’s propensity to alter the activity of a CYP in vivo (R2?=?0.97).
Therefore, this cocktail-substrate assay is considered to be a powerful tool for evaluating mechanism-based inhibition at an early stage of drug development.
This study compared the hepatic glucuronidation of Picroside II in different species and characterized the glucuronidation activities of human intestinal microsomes (HIMs) and recombinant human UDP-glucuronosyltransferases (UGTs) for Picroside II.
The rank order of hepatic microsomal glucuronidation activity of Picroside II was rat > mouse > human > dog. The intrinsic clearance of Picroside II hepatic glucuronidation in rat, mouse and dog was about 10.6-, 6.0- and 2.3-fold of that in human, respectively.
Among the 12 recombinant human UGTs, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 catalyzed the glucuronidation. UGT1A10, which are expressed in extrahepatic tissues, showed the highest activity of Picroside II glucuronidation (Km?=?45.1 μM, Vmax?=?831.9 pmol/min/mg protein). UGT1A9 played a primary role in glucuronidation in human liver microsomes (HLM; Km?=?81.3 μM, Vmax?=?242.2 pmol/min/mg protein). In addition, both mycophenolic acid (substrate of UGT1A9) and emodin (substrate of UGT1A8 and UGT1A10) could inhibit the glucuronidation of Picroside II with the half maximal inhibitory concentration (IC50) values of 173.6 and 76.2 μM, respectively.
Enzyme kinetics was also performed in HIMs. The Km value of Picroside II glucuronidation was close to that in recombinant human UGT1A10 (Km?=?58.6 μM, Vmax?=?721.4 pmol/min/mg protein). The intrinsic clearance was 5.4-fold of HLMs. Intestinal UGT enzymes play an important role in Picroside II glucuronidation in human.
Pharmacokinetic and metabolism aspects of AMG 222 interaction with target enzyme, dipeptidylpeptidase IV (DPPIV) were investigated.
Inhibition of recombinant human DPPIV by AMG 222 was measured. IC50 decreased as preincubation time increased. koff, kon and Kd were measured. Dilution assay indicated a long dissociation half-life (730?min) relative to DPPIV inhibitor vildagliptin. AMG 222 is a slow-on, tight-binding, slowly reversible inhibitor of DPPIV.
Amide and acid metabolites arising from hydrolysis of AMG 222’s cyano group were formed slowly by rhDPPIV, but not by microsomes or S9. The amide metabolite was converted to the acid metabolite by rhDPPIV, but not by an active site mutant. These metabolites of AMG 222 are formed by target-mediated metabolism of the cyano group, similar to vildagliptin.
Human plasma protein binding of [14C]AMG 222 was saturable and concentration-dependent. After 30?min, [14C]AMG 222 was 80.8% bound at 1?nM and binding decreased to 29.4% above 100?nM. The plasma DPPIV concentration (4.1?nM) and human plasma AMG 222 concentrations that inhibit DPPIV, occurred in the range of concentration-dependent binding. Target-mediated drug disposition influences AMG 222 pharmacokinetics, similar to DPPIV inhibitor, linagliptin.
Toremifene is an effective agent for the treatment of breast cancer in postmenopausal women and is being evaluated for its ability to prevent bone fractures in men with prostate cancer taking androgen deprivation therapy.
Due to the potential for drug–drug interactions, the ability of toremifene and its primary circulating metabolite N-desmethyltoremifene (NDMT) to inhibit nine human cytochrome P450 (CYP) enzymes was determined using human liver microsomes. Induction of CYP1A2 and 3A4 by toremifene was also investigated in human hepatocytes.
Toremifene did not significantly inhibit CYP1A2 or 2D6. However, toremifene is a competitive inhibitor of CYP3A4, non-competitive inhibitor of CYP2A6, 2C8, 2C9, 2C19 and 2E1 and mixed-type inhibitor of CYP2B6. CYP inhibition by NDMT was similar in magnitude to toremifene. Toremifene did not induce CYP1A2 but increased CYP3A4 monooxygenase activity and gene expression in drug-exposed human primary hepatocytes.
Although clinical doses of toremifene produce steady state exposures to toremifene and NDMT that may be sufficient to cause pharmacokinetic drug–drug interactions with other drugs metabolised by CYP2B6, CYP2C8, CYP3A4, CYP2C9 and CYP2C19, these data indicate that toremifene is unlikely to play a role in clinical drug–drug interactions with substrate drugs of CYP1A2 and CYP2D6.