Perspective Current Drug Metabolism, 2019, Vol. 20, No.

9 697

PERSPECTIVE

Concept of Drug Metabolism in Drug Discovery Pipeline

Syed Sayeed Ahmad1 and Mohammad A. Kamal2,3,4

1
Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, India; 2King Fahd Medical Research Center,
King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Kingdom of Saudi Arabia; 3Enzymoics, 7 Peterlee Place, Hebersham,
NSW 2770; 4Novel Global Community Educational Foundation, Australia

Drug discovery (DD) is a time-consuming and costly process. Approximately, it takes more than10 years with $2.6 billion to develop a
new drug [1], because it is an extremely complicated process involving scientists from various areas. In preclinical research, it involves me-
dicinal chemistry, biology, pharmacology, drug metabolism (DM), pharmacokinetics, formulation and toxicology. DM plays an important
role in deciding the pharmacological and toxicological impacts of medication in human [2]. Metabolism of drugs in the body is an unpredict-
able biotransformation process where drugs are essentially changed to different metabolites by different metabolizing enzymes [3]. The es-
sential site of DM is the smooth endoplasmic reticulum of the liver cell because of the presence of a lot of numerous enzymes. The DM hap-
pening in the liver is termed as hepatic metabolism whereas additionally the term hepatic digestion is used for DM occurring in other organs
of the body. Alternate destinations of drug metabolism include lungs, placenta, kidney, epithelial cells of gastrointestinal tract, adrenals and
skin [4]. Numerous small drugs are utilized by cytochrome P450 (CYP) enzyme in the body. CYPs, a group of key enzymes of hepatocytes of
endoplasmic reticulum, play a daunting role in oxidation and reduction mediated biotransformation, including carbon hydroxylation, heteroa-
tom oxidation, bond oxidation, hydrocarbon desaturation, halocarbon dehalogenation, etc. [5].
The human intestinal mucosa is a crucial place for absorption, distribution, metabolism and excretion (ADME)/Tox investigation for
medication improvement is hard to recapitulate in vitro [6]. Absorption is a process in which the drugs transfer from the sites of administra-
tion to systemic blood circulation. Distribution is related to protein/tissue binding and the exchange of the drugs among various spaces in the
body. Metabolism is the biotransformation procedure that usually proselytes the medications to more water-dissolvable atoms, encouraging
their discharge from the body. Excretion is the expulsion of drug and their metabolites from the body, typically through the urinary or biliary
pathways. It has been realized that drug-metabolizing enzymes (DMEs) and membrane transporters play a vital role in the ADME processes
[7].
Various in vitro techniques have been utilized in the drug choice procedure for surveying the intestinal absorption of drug candidates.
Among them, Caco2-cell and Madin-Darby canine kidney (MDCK) cell model have been recommended as solid in vitro models for the an-
ticipation of oral medication absorption. In absorption, this module gives forecast models to in vitro Caco2-cell [8] and MDCK cell measure
[9].
DMEs has a crucial role in the metabolism, elimination, detoxification of xenobiotics and drugs assimilation into the body. Most of
the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and
phase III transporters, which are present in abundance either at the basal unstimulated level or inducible at an elevated level after exposure to
xenobiotics [10, 11]. The metabolism of medications in the body can be interceded by enzymes in charge of phase I (oxidation, decrease,
hydrolysis) and additionally phase II (conjugation) biotransformation. Among these, the CYP enzymes are notable for their role in phase I
oxidative metabolism; enzymes known for phase II metabolism include N-acetyl transferase, uridine 50-diphospho-glucuronosyltransferases
(UGT), glutathione S-transferase (GST) and sulfotransferase (SULT) [12].
Drug transporters are generally transmembrane proteins that encourage the vehicle of vast or potentially ionized atoms all through the
cells. Phase III pathway is ordered into 2 elementary super-families: ATP-binding cassette (ABC) and solute carrier (SLC) transporters. ABC
transporters are subject to the energy (ATP) utilization to effectively take-up or efflux the medication from one side of the cell membrane to
another, though SLCs encourage the passage of specific solutes (eg, sugars and amino acids) over the membrane and effectively transport
different solutes against their electrochemical gradients by coupling the procedure with other solute or particle. They are available in numer-
ous areas, for example, liver, kidney, digestive system and cerebrum [13]. Oral administration is the most commonly used route for drug
treatment. Intestinal CYP-interceded metabolism can remove some orally regulated medications which have previously achieved fundamental
circulation while allowing the entry of different drugs unimpeded. A thorough understanding of the capacity of intestinal P450 enzymes to
utilize different clinical medications in people and preclinical species, including identification of the CYP enzymes expressing their control,
and the general significance of intestinal digestion contrasted with hepatic metabolism, is essential for improving the bioavailability of current
drugs and development of new drugs. Changeability in the activity of hepatic drug metabolism using CYP enzyme plays a causal role in lethal
cases and is in this way of immense interest. The CYP frameworks include a vast group of compounds that are crucial for hepatic DM in peo-
ple [14, 15].
In the drug disclosure process, DM assumes a major role and determines the fate of prospective drugs. DM must take place only after the
drugs have reached their specific target site and produced the desired effects. Moreover, the nature of the metabolites created from the
medication must be completely contemplated;otherwise, the drugs should be rejected during the screening procedure. DM is a noteworthy
measure in the high-throughput screening of planned medications. DM is an imperative procedure for the expulsion of undesirable substances
from the body. Anomalous medication digestion profile can prompt perilous difficulties. Different diseases may possibly change the meta-

1875-5453/19 $58.00+.00 © 2019 Bentham Science Publishers

698 Current Drug Metabolism, 2019, Vol. 20, No. 9 Perspective

bolic profile of medication by modifying the articulation and capacity of key enzymes. Care must be practiced while recommending different
prescriptions to patients with specific illnesses, which can adjust sedate pharmacokinetics profiles.
The titles of subtopics published in volume I & II of the special issue of CDM are mentioned in Table 1 & 2, respectively. From these
titles, it is clear that this special issue of CDM on “Global Trends in Nanotechnological Approaches for Various Health Issues – Volume I &
II” is of broad scientific interest across a number of fields and is well worth reading. In these volumes of the special issue for CDM, authors
contributed further on the current progress and future outlook of different nanotechnological approaches on public issues. This volume in-
cludes the examples of different exciting nanotechnological strategies for diagnosis and management of NDs, particularly Alzheimer’s dis-
ease, Parkinson’s disease, cancer and type 2 diabetes mellitus which broaden our vision of the utility of nanotechnological approaches in
medical sciences [16-20].
Table 1. The information of the published articles in the first special issue of CDM.

Corresponding
Affiliations Title Keywords Reference
Authors

King Fahd Medical Epilepsy; Liposomes; Nano-

A synopsis of nano-technological
Research Center, King emulsions; Polymeric; Nanoparticles;
Mohammad approaches toward anti-epilepsy
Abdulaziz University, Saudi Solid-lipid;
Amjad Kamal therapy: present and future research
Arabia;/ Enzymoic, Nanoparticles; Magnetic; Nanoparti-
implications
Australia cles; Therapy

Department of Biochemis-
Therapeutic interventions for the Aβ peptide; Alzheimer’s disease;
try, Faculty of Life
Aabgeena Naeem suppression of Alzheimer’s Disease: Amyloid fibrils; Protein aggregates;
Sciences, Aligarh Muslim
Quest for a remedy Nanotechnological approach;
University, India

Center of Excellence in
Genomic Medicine Health; diseases; Gene therapy;
Mahmood Rasool Research, King Abdulaziz Nanoparticle-based therapy in genomics Nanoparticles;
University, Jeddah, Saudi Gold Nanoparticles; Cancer;
Arabia

Department of Nanobiotechnological approaches Nanotechnology; Multiple drug resis-

Shazi Shakil Bio-engineering, Integral against multidrug resistant bacterial tant bacteria, Nanoparticles; Staphylo-
University, India pathogens: An update coccus aureus; Antimicrobial drugs;

Faculty of Agrobased Recent advances in nanotechnology Characteristics of Nanomedicine; [21]

Pasupuleti
Industry, Universiti based diagnosis and treatments of dia- Diabetes; treatment; Glucose monitor-
Visweswara Rao
Malaysia Kelantan betes ing; Insulin administration

King Fahd Medical Application of proteomic tools in modern Nanotechnology; Neurological disor-
Research Center, Nanotechnological approaches towards ders; Proteomics; Nano techniques;
Ghulam Md Ashraf
King Abdulaziz University, the effective management of neurode- Nanoapplications;
Saudi Arabia generative disorders Nano-drugs; Disposition`

Center of Excellence
Recent developments in nanomedicines Nanomedicines; Cancer; Neurodegen-
in Genomic Medicine
Muhammad Imran for management of various health issues erative disorders; Gene therapy;
Research, King Abdulaziz
Naseer via metabolism and physico-chemical Liposomes; Quantum dots; Silver and
University, Jeddah,
properties gold nanoparticles
Saudi Arabia

Department of
Pharmaceutics, Graphene; Graphene oxide;
Utrecht Institute of Role of graphene nano-composites in Nanomedicine; Inorganic; Nanoparti-
Sohail Akhter Pharmaceutical cancer therapy: Theranostic applica- cles; Cancer therapy; Theranostics;
Sciences, Utrecht tions, metabolic fate and toxicity issues Metabolism; Disposition;
University, The Biodistribution and Excretion
Netherlands
Perspective Current Drug Metabolism, 2019, Vol. 20, No. 9 699

Table 2. The information of the published articles in the second special issue of CDM.

Corresponding
Affiliation Title Reference
Authors

Center of Excellence in Genomic Medicine

Research (CEGMR), Post Box No. 80216, King Scope and applications of nanomedicines for the
Mahmood Rasool
Abdulaziz University, Jeddah, 21589 management of multiple sclerosis
Saudi Arabia

EA3842 Homeostasie cellulaire et pathologies

The ins and outs of nanoparticle technology in neurodegen-
Cornelia M. Wilson and Chaire d'Excellence pneumologie experimen-
erative diseases and cancer
tale, Universite de Limoges, France

Utrecht Institute of Pharmaceutical Solid matrix based lipidic nano-approach in oral cancer
Sohail Akhter
Sciences Utrecht University The Netherlands chemotherapy: Application and pharmacokinetics

Institute of Life Sciences School of Science and

Sanjay Singh Nanotechnology in disease diagnostic techniques
Technology Ahmedabad University

Department of Informatics Ionian University, Application of efficient nanoparticles for early diagnosis and
Athanasios Alexiou [22]
Greece treatment of cancer

Department of Biochemistry
Nanoparticles, neurotoxicity and
Gohar Mushtaq College of Science, King Abdulaziz, University
neurodegenerative diseases.
Saudi Arabia

Department of Biosciences Integral University, Magnetic nanoparticles: Properties, synthesis and biomedical
Mohd Sajid Khan
India applications

An overview on global trends in nanotechnological

Ghulam Md. Ashraf King Abdulaziz University, Saudi Arabia
approaches for Alzheimer Therapy

Applications of nanotechnology in diagnostics and

Athanasios Alexiou Ionian University, Greece
therapeutics of Alzheimer’s and Parkinson’s disease

Mohammad Amjad King Fahd Medical Research Center, King An overview of current screening and management
Kamal Abdulaziz University, Saudi Arabia approaches for prostate cancer

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Mohammad A. Kamal
King Fahd Medical Research Center,
King Abdulaziz University,
P.O. Box 80216,
Jeddah 21589,
Kingdom of Saudi Arabia
E-mail: prof.ma.kamal@gmail.com