Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

High degree of pharmacokinetic compatibility exists between the five-herb medicine XueBiJing and antibiotics comedicated in sepsis care

Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding XueBiJing, a five-herb medicine, to antibiotic-based sepsis care. Although adding XueBiJing further reduced 28-day mortality modulating the host response, pharmacokinetic herb-drug interaction is a widely recognized issue that needs to be studied. Building on our earlier systematic chemical and human pharmacokinetic investigations of XueBiJing, we evaluated the degree of pharmacokinetic compatibility for XueBiJing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both XueBiJing‒antibiotic and antibiotic‒XueBiJing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study XueBiJing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no XueBiJing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could, due to their inhibition of uridine 5'-diphosphoglucuronosyltransferase 2B15, organic anion transporters 1/2 and/or organic anion-transporting polypeptide 1B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions (resulting in increased exposure) are likely desirable due to these XueBiJing compounds' low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from XueBiJing. Collectively, XueBiJing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.

Identification of human cytochrome P450 and UGT enzymes involved in the metabolism of ferulic acid, a major bioactive component in traditional Chinese medicines / 中国天然药物

Ferulic acid (FA) is an active component of herbal medicines. One of the best documented activities of FA is its antioxidant property. Moreover, FA exerts antiallergic, anti-inflammatory, and hepatoprotective effects. However, the metabolic pathways of FA in humans remain unclear. To identify whether human CYP or UGT enzymes are involved in the metabolism of FA, reaction phenotyping of FA was conducted using major CYP-selective chemical inhibitors together with individual CYP and UGT Supersomes. The CYP- and/or UGT-mediated metabolism kinetics were examined simultaneously or individually. Relative activity factor and total normalized rate approaches were used to assess the relative contributions of each major human CYPs towards the FA metabolism. Incubations of FA with human liver microsomes (HLM) displayed NADPH- and UDPGA-dependent metabolism with multiple CYP and UGT isoforms involved. CYPs and UGTs contributed equally to the metabolism of FA in HLM. Although CYP1A2 and CYP3A4 appeared to be the major contributors in the CYP-mediated clearance, their contributions to the overall clearance are still minor (< 25%). As a constitute of many food and herbs, FA poses low drug-drug interaction risk when co-administrated with other herbs or conventional medicines because multiple phase I and phase II enzymes are involved in its metabolism.

PBPK modeling and simulation in drug research and development

Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug-drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry, and has become an integral tool in drug discovery and development. In this mini-review, the concept and methodology of PBPK modeling are briefly introduced. Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development. These case studies are from our own work and the literature for better understanding of the absorption, distribution, metabolism and excretion (ADME) of a drug candidate, and the applications to increase efficiency, reduce the need for animal studies, and perhaps to replace clinical trials. The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.

Lipid Profiles and trans Fatty Acids in Serum Phospholipids of Semi-nomadic Fulani in Northern Nigeria.

The Fulani are semi-nomadic pastoralists of West Africa whose diet, culture, and economy are centred on cattle. Previous studies have shown that the Fulani of northern Nigeria derive 50% of their total calories from fat and 30% of their calories from milk, cheese, yogurt, and butter oil that contain significant amounts of trans fatty acids (TFAs), primarily vaccenic acid, which raise total serum cholesterol and low-density lipoproteincholesterol (LDL-C), and lower high-density lipoprotein-cholesterol (HDL-C). The study was conducted to know how the consumption of relatively large amounts of dairy products by adult Fulani affected the TFA content of their serum phospholipids. Blood samples were collected from 22 male and 29 female Fulani, aged 35-60 years, who were living in rural areas of Gombe state in northeastern Nigeria. The total serum phospholipid fraction was isolated, and its fatty acid composition was determined. Surprisingly, vaccenic acid was not detected, and three other TFAs—18:1-t6, 18:1-t9, and 18:2-t9,t12—together accounted for only 0.16% of the total fatty acid. The mean serum total cholesterol, LDL-C, and triglyceride concentrations of the subjects were within the normal range for populations in developed countries; however, at 32 mg/dL, the mean serum HDL-C concentration of the Fulani males was slightly below the lower limit of the reference range. No correlations were observed between the total TFA percentage or that of the three individual TFAs and any of the parameters of the serum lipid profile. These findings indicate that, with respect to TFAs at least, the fatty acid pattern of the serum phospholipids of Fulani pastoralists does not reflect the high TFA content of their traditional diet. Despite the consumption of rumenic acid-rich dairy products, for unknown reasons, the semi-nomadic Fulani manage to maintain a low level of TFAs in their blood and a relatively healthful serum lipid profile. While the mechanism that accounts for this disconnect between the consumption of TFAs by Fulani pastoralists and the proportion of TFAs in their serum phospholipids is obscure, possibilities include discrimination against rumenic acid during the process of triglyceride synthesis and chylomicron synthesis in the intestine and the preferential oxidation of TFAs by Fulani the people compared to other ethnic groups.