Many drugs with specific functional moieties, including esters, amides, thioesters, epoxides, sulfates, and glucuronides can be metabolized by adding water. Hydrolysis is generally carried out by the corresponding enzymes, such as esterase or amidases. Prodrug design has received increasing interest, thereby leading to considerable attention to the important roles of hydrolytic metabolism. The majority of in vivo biotransformations are oxidation, while reductive reactions preferentially occur in anaerobic or low-O conditions.
3. Trends in drug–drug interactions of therapeutic biologics
Use of mass defect filter and isotope pattern filter can also limit false positives and narrow down the search to the products which are authentically related to the parent drugs. Overall, use of the multi-dimensional automated systems improves the efficiency and productivity in metabolite profiling, by thoroughly interrogating the vast amount of information acquired from UHPLC-HRMS. Nevertheless, the experience and knowledge of biotransformation scientists represent the key factor to ensure successful and comprehensive characterization of metabolic pathways. Investigation of herb–drug interactions (HDIs) is often more complicated than that on DDIs, due to the complex herbal components and the batch-to-batch variation of herbal products. More pharmacokinetic and pharmacodynamic data on the bioavailable herbal components from clinical studies using standardized herbal products are warranted for better understanding of HDIs. With the increasing number of therapeutic biologics in the market, it is critical to build strategies and regulations on the potential DDIs involved biologics.
1. The current status and challenges of PBPK modeling
Recently, mathematical modeling, particularly physiologically-based pharmacokinetic (PBPK) modeling has also been applied to investigate potential pharmacokinetic-based DDIs. A recent review by Min et al.152 depicted how pharmacokinetic modeling improves and simplifies the investigation on DDIs. In addition, systematic reviews and databases summarize all the experimental and predicted data on DDIs, which are useful for providing warning and proper advice to patients in clinical practice153. As previously discussed in this chapter, medications that are swallowed or otherwise administered into the gastrointestinal tract are inactivated by the intestines and liver, known as the first-pass effect.
Phases of detoxification
- A recent study revealed that moringa oleifera seed oil could limit gentamicin-induced oxidative nephrotoxicity29.
- Dose response is the dose of medication required to achieve the desired response to the medication.
- The pH of the mixed oral fluid usually is around 6.6–6.8, not elevated as might be anticipated.
- In the idealized model, the same amounts of inert and toxic products are generated in all three species.
The amount of the metabolite isolated can be calculated from the specific radioactivity of the drug (see Section 8.2). In summary, PBPK can be utilized to mechanistically understand and predict a priori in vivo pharmacokinetic characteristics from a whole body perspective by integrating system-specific and drug-specific parameters. PBPK modeling has been routinely conducted for new entities to illustrate pharmacokinetic characteristics when drug–drug interactions happen or when dosing in specific populations needs optimization. The predictive performance of CYP3A- and CYP2D6-mediated DDI was found to be best for new drugs as victim using PBPK method, which could be applied to waive part of clinical trial. Due to unclear changes in transporter-mediated mechanism and system-specific parameters in specific populations, PBPK modeling power is limited to supporting clinical trial design.
Associated Data
However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the glyoxalase system, which acts to dispose of the reactive aldehyde crack cocaine symptoms and warning signs methylglyoxal, and the various antioxidant systems that remove reactive oxygen species. The US FDA has produced a guideline for safety testing of drug metabolites [127]. Generally, metabolites of concern (ie, major metabolites) are those formed in humans at greater than 10% of the parent drug exposure at steady state [127]. While exogenously supplied S9 may form some of the metabolites in vitro, the quantity formed is often insufficient for qualification.
Most drugs are mainly cleared from the body through metabolizing enzyme-mediated processes34. Some metabolizing enzymes (e.g., CYP2D6, 2C9 and 2C19, etc.) are polymorphic in nature and exist in two or more variant forms with different enzymatic activity in different individuals. Poor metabolizers (individuals with low or no enzymatic activity) could have much higher drug exposure than extensive metabolizers (individuals with high enzymatic activity) when a given dose of a drug is administered. 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.
In addition to UGTs, sulfonyl transferases (SULTs) and glutathione S-transferases (GSTs) are also important conjugative enzymes mediating phase II reaction. Recently, UGT1A3 was found to be involved in the glucuronidation of alpinetin41. Other UGT isoforms involved endogenous and exogenous substrates are listed in Table 223,43, 44, 45, 46.
Interestingly, diabetes mellitus showed a tissue-specific effect on CYP3A expression and activity (induced in liver and inhibited in intestine), resulting in opposite pharmacokinetic behavior for verapamil after oral and intravenous administration to diabetic rats212. UGTs, the major phase II conjugation enzymes, can also be affected by diabetes mellitus. It was reported that the UGT1 family is adaptively upregulated in the diabetic gastrointestinal tract199.
In addition, acyclovir, an antiviral drug, was also a substrate of OAT1/3 and JBP485 can inhibit its renal excretion95. Furthermore, the DDIs between JBP485 and entecavir through the competitive inhibition precipitated withdrawal: definition symptoms traits causes of OAT1 and OAT3 significantly decreased the renal excretion of both compounds96. Probenecid, by inhibiting OAT1 and OAT3, reduced the accumulation of cephaloridine and subsequently nephrotoxicity97,98.
For example, pain relievers may be administered directly into the bloodstream (referred to as intravenous medications) so they are quickly available for distribution to tissues within the body. Pharmacodynamics refers to the effects of drugs in the body and the mechanism of their action. As a drug travels through the bloodstream, it exhibits a unique affinity for a drug-receptor site, meaning how strongly it binds to the site. Drugs and receptor sites create a lock and key system (see Figure 1.1[1]) that affect how drugs work and the presence of a drug in the bloodstream after it is administered.
The most obvious approach is to increase the size of the EC cell and the electrodes, but, in practice, many other related parameters do not scale well, often leading to disappointing metabolite product yields, in both relative and absolute terms. Commercially available EC cells share some technical drawbacks when scaled up, such as a high IR drop, low mass transport and low conversion yields due to cell geometry, which must be addressed in future cell designs for better scalability. In addition, the fabrication of physically and chemically stable electrodes with low adsorption properties and an effective surface area (of the order of 100 cm2) that can be used in a reasonable cell volume of about 100 mL is required for metabolite synthesis. Other options are large surface area porous or nanoporous electrode materials that are cheap enough to be disposable.
Together, these studies demonstrate the capability of IM-MS in the separation of positional isomers that commonly arise from drug metabolism. 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.
Other medications have a longer half-life (and therefore are eliminated more slowly from the body, resulting in longer therapeutic duration) and may only be administered once or twice per day. For example, oxycodone immediate release is prescribed every 4 to 6 hours for the therapeutic effect of immediate relief of severe pain, whereas oxycodone ER (extended release) is prescribed every 12 hours for the therapeutic effect of sustained relief of severe pain. Agonistic and antagonistic effects on receptors for common classes of medications are further discussed in the “Autonomic Nervous System” chapter. Safely administering medications to clients is a significant concern and requires team effort by pharmacists, prescribing health care providers, and nurses. In addition to the factors described in this chapter, there are many other considerations for safe medication administration that are further explained in the “Legal/Ethical” chapter. Some medications inadvertently bypass the blood-brain barrier and impact an individual’s central nervous system function as a side effect.
The impact of protein binding and transporter on PK and PD properties of drug candidates are beyond the scope of this review. Drug discovery is an extremely complicated process involving scientists from various areas. In preclinical research, it involves medicinal chemistry, biology and pharmacology, drug metabolism and pharmacokinetics, formulation, and toxicology.
It was noted that the presence of a certain type of bacteria may have an impact on chemotherapy and immunotherapy181,182. Clinical trials are currently conducted on microbiota interventions, such as probiotics and fecal microbiota transplant (FMT), to explore their influence on the efficacy and toxicity of co-administrated chemotherapeutic agents, immunotherapeutic agents and anti-inflammatory drugs183. The potential benefits of probiotics and FMT to increase the efficacy of pembrolizumab in the treatment of PD-1 resistance patients184 and to reduce the adverse effects of aspirin185 and irinotecan186 are currently under clinical investigation. Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, decyclization, and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver.
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.
For example, PBPK modeling of two major active components from Wuzhi capsule (Schisandra sphenanthera extract) predicts its interaction with tacrolimus metabolism by CYP3A4 inhibition158. However, the application of modeling and simulation on the investigation of HDIs is still restricted by the aetna insurance coverage for drug rehab limited human pharmacokinetic data of herbal components152. More sophisticated designs of clinical studies are warranted to evaluate the safety and efficacy of the concomitant use of herbs and drugs. Renal clearance of drugs consists of glomerular filtration, tubular secretion and reabsorption.
