A recent review by Aspromonte et al.217 has summarized a comprehensive modulation of cardiac CYP in patients with HF. In general, cardiac CYP1B and CYP2A, CYP2B, CYP2J, CYP4A and CYP11 mRNA levels and related enzyme activities are usually increased in HF217,218. On the other hand, HF plays an important role in the down-regulation of hepatic CYP involved in drug metabolism through several mechanisms which include hepatocellular damage, hypoxia, elevated levels of pro-inflammatory cytokines, and increased production of heme oxygenase-1219. For example, the plasma concentrations of caffeine (CYP1A2 probe), mephenytoin (CYP2C19 probe), dextromethorphan (CYP2D6 probe) and chlorzoxazone (CYP2E1 probe) were significantly elevated in patients with congestive HF203.
- Plasma binding of these oligomers can sometimes be very high and has been reported to affect their distribution and clearance160.
- Investigation of HDIs is often more complicated than those of DDIs, due to the complex herbal components and the batch-to-batch variation of herbal products.
- In a hospital setting, nursing staff monitors for signs of a toxic buildup of metabolites or active drugs.
- Therefore, PBPK analysis can estimate in vivo dissolution characteristics more accurately, which will be useful to guide drug development278,279.
The substrates of BCRP include statins (pitavastatin, rosuvastatin), antiviral drugs (lamivudine, zidovudine, abacavir), anticancer drugs (methotrexate, SN-38, irinotecan, gefitinib, imatinib, erlotinib) and antibiotics (nitrofurantoin, ciprofloxacin)84. The efflux transporter MRP2 is also expressed on the brush border membrane of the intestine and transports a variety of substrates conjugated with sulfate, glutathione and glucuronide, as well as various unmodified drugs. Previous studies showed that resveratrol inhibited MRP2 and thereby increased the intestinal absorption of methotrexate85. how to find a faith-based rehab near you Hepato-intestinal drug metabolism is highly variable not only among patients but even in one particular individual over time. It is lower immediately after birth, in carriers of inactivating mutations in drug metabolizing enzymes, in patients treated with drugs inhibiting these enzymes (e.g. macrolids and conazols), and in those with liver disease or insufficient hepatic blood flow. It is higher in patients treated with transcriptional inducers of drug metabolizing enzymes, e.g. with rifampin or carbamazepine and, in the case of CYP2D6, in the presence of additional gene copies.
In some cases where bioactivation is believed to likely be one of the causes for observed genetoxicity, trapping studies of drugs with DNA or DNA bases might be performed to elucidate the structures of reactive metabolites formed in biological systems. For example, the above mentioned new lead compound 46 showed genetoxicity in chromosomal aberration assay in Chinese hamster ovary (CHO) cells in vitro and micronucleus induction assay in mouse bone marrow in vivo. Subsequent in vitro trapping studies using DNA bases indicated that up to five adenine adducts were detected in incubations of 46 with human and monkey liver microsomes or recombinant human CPY3A449. Based on the LC–MS/MS and NMR data, the major adenine adduct 50 has a cyclized structure (Scheme 5).
Factors affecting drug metabolism
This further confirmed the existence of the reactive ring-opened para-quinone intermediate 47 as discussed above. A single cell gel electrophoresis assay (Comet assay) in human hepatocytes further indicated that 46 caused DNA damage in a dose-dependent manner49. The PBPK modeling method is not an independent modeling method, and sometimes it is better to be integrated with other modeling methods for better results.
The liver’s primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes. The level of these cytochrome P-450 enzymes controls the rate at which many drugs are metabolized. The capacity of the enzymes to metabolize is limited, so they can become overloaded when blood levels of a drug are high (see Genetic Makeup and Response to Drugs Genetic Makeup and Response to Drugs ).
The role of the liver in drug metabolism
PXR and CAR not only regulate the transcription of drug-metabolizing enzymes and transporters, but also orchestrate energy metabolism and immune responses231. In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid. Sites on drugs where conjugation reactions occur include carboxy (-COOH), hydroxy (-OH), amino (NH2), and thiol (-SH) groups. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce active metabolites. The addition of large anionic groups (such as GSH) detoxifies reactive electrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.
Activation of LXR prevents lipopolysaccharide-induced lung injury by regulating antioxidant enzymes and the implication of this regulation is pulmonary tissue protection237. Moreover, a recent study demonstrated that activation of LXR attenuates OA-induced acute respiratory distress syndrome by attenuating the inflammatory response and enhancing antioxidant capacity238. PPARα induces the expression of CYP4A in response to a heterogeneous group of peroxisome proliferators. stopping cymbalta PPARγ also regulates the expression of CYP4V2, a fatty acid metabolizing enzyme, in human tetrahydropyranyl 1 (THP1) macrophages60. Because metabolic enzyme systems are only partially developed at birth, newborns have difficulty metabolizing certain drugs. As people age, enzymatic activity decreases, so that older people, like newborns, cannot metabolize drugs as well as younger adults and children do (see Aging and Drugs Aging and Medications ).
Thus, most marketed recombinant P450 enzymes generally contain cytochrome-b5 and POR to enhance their oxidative efficiencies. In some cases, POR alone can also catalyze one-electron reduction, such as with aristolochic acid324. Another reported substrate of POR is an aldehyde intermediate (M-CHO) that is formed during the metabolism of imrecoxib, which is a moderate COX-2 inhibitor325. POR expresses dual effects on further M-CHO metabolism, namely oxidation to form carboxylic acid metabolite (M2) and unexpected reduction to form a hydroxymethyl metabolite (M1), by donating electrons to P450s or competitively to the substrate, respectively (Fig. 4A). The two opposite metabolic pathways, especially M-CHO reduction, led to an underestimation of the amount of M2 in static in vitro incubations. In addition to the above applications, the PBPK modeling method also could be used to predict first-in-human PK profiles286.
1. Species difference in metabolism of drugs
Efflux transporters expressed on the brush border membrane of the intestine, are considered as the barriers for intestinal drug absorption. P-gp, the most studied efflux transporter, has broad substrate specificity and significantly limits the bioavailability of many oral drugs79. For example, co-treatment with verapamil, a P-gp inhibitor, increases the intestinal absorption of afatinib or bestatin due to P-gp inhibition in the intestine80,81. On the contrary, rifampin, a P-gp inducer, decreases the oral absorption of cyclosporine and tacrolimus through the induction of P-gp in the intestine82. BCRP is another efflux transporter expressed in the intestine and suppresses the intestinal absorption of drugs83. Due to only one ATP binding site and six putative transmembrane helices, BCRP is considered a “half-transporter”.
Along with the coadministration of herbal or natural products, the potential herb–drug interaction is gaining increasing attention, and can be predicted using a PBPK modeling method. But accurate prediction of herb–drug interactions is still a challenging mission because of the complex composition and relatively limited knowledge of individual constituents that produce the interactions. A feasible procedure is to firstly identify the major constituents followed by compound–compound interaction prediction as previous introduced158,298.
In the case of prodrugs where metabolizing enzymes are required to transform prodrugs to active drugs, the concentrations of active drugs could be lower in poor metabolizers than that in normal patients, resulting in less optimal therapeutic effects. Thus, drug candidates which are mainly metabolized by a polymorphic enzyme could have different pharmacological and toxicological effects among poor metabolizers and extensive metabolizers. Codeine is a prodrug that only weakly binds to the opioid receptors for analgesic effect. Polymorphic enzyme CYP2D6 catalyzes the O-demethylation of codeine to the active drug morphine 34 (Fig. 4) which has 200-fold greater affinity than codeine. Poor metabolizer patients with low CYP2D6 activities have lower levels of morphine, resulting in less optimal analgesic effect. However, ultrarapid metabolizer patients with higher CYP2D6 activities can have much higher levels of morphine.
2. Effects of endogenous metabolism mediated by nuclear receptors on diseases
In the cell genome, the key technologies of this method include the acquisition of embryonic stem cells, the design of target, and the screening of embryonic stem cells. Homologous recombination is time-consuming, costly, as well as inefficient in gene editing, and may lead to adverse mutations. As it is difficult to obtain and culture embryonic stem cells in rats, the construction and application of knockout or knock-in rat models have lagged behind the mouse models.
However, when most of the enzyme sites are occupied, metabolism occurs at its maximal rate and does not change in proportion to drug concentration; instead, a fixed amount of drug is metabolized per unit time (zero-order kinetics). In this case, if 500 mg is present in the body at time zero, after metabolism, 450 mg may be present at 1 hour and 400 mg at 2 hours (illustrating a maximal clearance of 50 mg/hour and no specific half-life). As drug concentration increases, metabolism shifts from first-order to zero-order kinetics.
Based on the current findings on pharmacokinetic- and pharmacodynamic-based DDIs of therapeutic biologics, assessments on the modulation of CYP activity and immunogenicity, and identification and monitoring of clinical endpoints of the therapeutic biologics is recommended. In addition to consideration of classical PK and pharmacodynamics interactions, microbiota-mediated HDIs/DDIs are expected to bring additional insight into their interactions. Novel experimental and computational strategies, such as gnotobiotic animal models and physiologically-based pharmacokinetic modeling can be incorporated in future investigations on microbiota-mediated HDIs/DDIs. Recent studies on miRNA regulation in DMPK also led to the development of novel research approaches and technologies. Using this RNA EMSA and other methods, a number of CYP genes (e.g., CYP2C19, CYP2E1 and CYP2D6) and regulators have been shown to be regulated post-transcriptionally by particular miRNAs121, 122, 123, 124, 125.