Bioequivalence & Bioavailability International Journal

Basics of Biopharmaceutics: A Mini Review

Lakshmana Prabu S1* and Suriyaprakash TNK2

1Department
Mini Review
of Pharmaceutical Technology, Bharathidasan Institute of Technology,
Volume 1 Issue 1
Anna University, Tiruchirappalli, India
Received Date: May 10, 2017
2Department of Pharmaceutics, Al Shifa College of Pharmacy, Kerala, India Published Date: June 29, 2017

*Corresponding author: Lakshmana Prabu S, Department of Pharmaceutical

Technology, Bharathidasan Institute of Technology, Anna University, Tiruchirappalli, India, Tel: +919750550965;
Email: [email protected]

Abstract
Drug research is a unique multi-disciplinary process towards the development of novel therapeutic agent to meet the
current global medicinal needs. Drug discovery and development are the two major stages in drug research. Drug
discovery includes new target identification and characterization, synthesis of new lead molecules, physicochemical
characterization and screening of the lead molecule for its biological activity through in vitro and in vivo techniques.
Drug development stage includes the assessment of its safety and toxicity of the developed new drug molecule. Drug
molecules are substance used for diagnosis or treating for various diseases. Drugs can be given in different dosage
form such as solids, semisolids, liquids, topical and parenteral preparation to produce the desired therapeutic activity
and to meet the patient's needs. Biopharmaceutics is a major branch in pharmaceutical sciences describes the role of
dosage form in the absorption and disposition of drugs in the body which are assessed through pharmacodynamic
and pharmacokinetic parameters or properties. Pharmacodynamics correlates the concentration of the drug with its
therapeutic and toxicological effect. Pharmacokinetics correlates how the drug moves through the human body by its
four main pathways such as absorption, distribution, metabolism and elimination and measuring the drug
concentration in biological matrices.

Keywords: Pharmacokinetics; in vitro and in vivo; Pharmacodynamics; Bioavailability; Endocytosis

Introduction
Drug discovery and development are the two major is composed as series of membrane barriers which are
stages in drug research to meet the current global divided into compartment filled with aqueous
medicinal needs. Target identification and its components. These membrane barriers are composed
characterization, synthesis of new chemical entity and of phospholipid bilayers; these phospholipid
its characterization, evaluation of biological activity membranes consist of head group (polar) and tail
through in vitro and in vivo techniques are involved in groups (non-polar). Drugs lipophilicity and partition
drug discovery. To develop a new chemical entity coefficient are important for membrane permeability
around 10-14 years are needed with an average cost of [3,4].
more than $800 million. Success rate of the drug
discovery and development is approximate of 0.01% [1
out of 10,000 screened compounds] [1,2]. Human body

Basics of Biopharmaceutics: A Mini Review Bioequiv & Bioavailab Int J

2
Bioequivalence & Bioavailability International Journal

Biopharmaceutics Drugs can be absorbed after crossing the biological

membrane. Drugs can cross the biological membrane
Biopharmaceutics is a major branch in either transcellular or paracellular mechanism [5,12].
pharmaceutical sciences which has an important role in
drug discovery and development to ensure the Drug transport across cell membranes:
therapeutic efficiency of the developed drug molecule.
Biopharmaceutics links pharmacodynamic and 1. Passive diffusion: In Passive diffusion, the drug
pharmacokinetic properties of the drug substance. In transport across the cell membrane based on the
short, biopharmaceutics mainly involves drug concentration gradient which provides energy. In
absorption process. The other parameters like aqueous passive diffusion process drug in the form of
solubility, stability, permeability and first pass effect are unionized form is absorbed in higher concentration
also concern in biopharmaceutics [5,6]. Knowledge of than ionized form.
biopharmaceutics is crucial to adjust the drug dosing 2. Active transport: In active transport, drug
among the different species and also the role of drug molecules move across the cell membrane from the
does to the body and what body does to the drug [7,8]. lower concentration to higher concentration by
utilizing the chemical energy.
Pharmacodynamics 3. Endocytosis: In endocytosis, molecules are
absorbed by engulfing by utilizing energy.
Pharmacodynamics correlates the concentration of
the drug with its therapeutic and toxicological effect. The other endocytosis type processes are exocytosis,
phagocytosis and pinocytosis [11,13-14].
Pharmacokinetics
Pharmacokinetics deals with the measurement of Evaluation techniques of drug absorption: The rate
drug concentration in biological matrices by selective and extent of drug absorption can be evaluated through
and sensitive bioanalytical methods based on the drug’s various in vitro and in vivo techniques.
absorption, distribution, metabolism and excretion
(ADME). Understanding of pharmacokinetic properties Human colon adenocarcinoma cell lines Caco-2, HT-
is important in drug discovery and development 29 and MDCK are commonly utilized to assess the drug
process; poor pharmacokinetic properties of any drug absorption. Other in vitro models utilized to assess the
has exclusive role in termination from further studies drug absorption are cell culture models, isolated
[1,9,10]. mucosal cells, brush border membrane vesicles, isolated
tissue techniques and everted tissue techniques
Pharmacokinetic parameters includes everted sac technique and intestinal rings [15-
18].
Absorption: Concentration of drug in the blood and
other biological matrix after drug administration
Distribution
reflects the absorption of the drug. Absorption of the
drug also reflects the solubility as well as the crystal Distribution gives information about the time
nature of the drug. duration of drug in tissue or organs. In simple way
distribution is a reversible transfer of drug within the
Various factors which affect the absorption of the drug body from one location to another. Lipophilicity and
are: protein binding are the two factors having an important
1. Physicochemical characteristics of the drug role drug distribution in the body. Lipophilic drugs will
2. Formulation factors get accumulated in organs and tissues whereas
3. Physiological factors affecting bioavailability [6,11]. hydrophilic drugs will get accumulated in cells.

Absorption of Drug: Drugs are either weak acid or Distribution of the drug is depends upon the
base in nature; it exist both ionized and non-ionized following factors, such as:
forms in the body. In membrane lipids, non-ionized  Blood flow to the tissue
form of drug is sufficiently soluble and it can cross the  Ratio between tissue/blood
biological cell membrane. The protonated form is  Apparent Volume of Distribution
predominates when the pH is less than pKa, whereas  Protein binding
non-protonated form is predominates when the pH is  Lipid solubility
greater than pKa. When weak acid drugs are protonated  Molecular Size
it becomes non-ionized form and readily absorb in  Ionization of drug
stomach, when weak basic drugs are protonated it  Permeation across the cell membrane
becomes ionized and readily absorb in the intestine. Compartment models in drug distribution

Lakshmana Prabu S and Suriyaprakash TNK. Basics of Biopharmaceutics: Copyright© Lakshmana Prabu S and Suriyaprakash TNK.
A Mini Review. Bioequiv & Bioavailab Int J 2017, 1(1): 000103.
3
Bioequivalence & Bioavailability International Journal

After administration, distribution of drug in a epoxide hydrolases, alcohol dehydrogenases,

biological system can be explained through hypothetical esterase and methyltransferases.
structures as compartment models. iii. Cellular systems - Cellular system is used to
assess the drug metabolism, permeation of
Various pharmacokinetic compartment models in drug across the cell membrane, enzyme
drug distribution are: stimulation and cytotoxicity.
 One-compartment model iv. Organ slices – Various organ slices such as
 Two-compartment model liver, brain, heart and kidney are used to
 Multi-compartment model [19-21]. assess its biochemical process.

Drug Metabolism 2. In vivo method

Drug metabolism is conversion of drug into its
i. Radionuclides – Radionuclides such as Tritium
metabolites either active or inactive through enzymes.
(3H) and Carbon14 (14C) are used to assess the
In simple way drug metabolism is a process to facilitate
drug metabolism [25,26].
the excretion of drug by converting the drug into less
polar or more polar and water soluble. Most of the
drugs are metabolized in the liver, which converts the Clearance
lipophilic drugs into hydrophilic drugs through Drug clearance (CL) is defined as the quantity of drug
metabolizing enzymes. Other organs involved in the cleared per unit time from the vascular compartment
metabolism of drugs through metabolizing enzymes are through metabolism and excretion. In general drugs are
gut, kidneys, brain, lungs and skin. extracted from the body through hepatic clearance and
Usually drug metabolism is carried out by two renal excretion.
processes such as:
Excretory organs
1. Phase I- Unmasking functional group like OH, NH2,
Major routes: Kidneys, Liver and Lungs
SH which facilitate the phase II conjugative
Minor routes: Skin, hair, sweat, saliva, tears and milk
reaction.
[6,11,27-30].
2. Phase II- Conjugation reaction with amino acid,
acetic acid, sulfuric acid and glucuronic acid and
convert the drug into more water soluble and Conclusion
readily excreted through urine or bile.
Drug research is a unique multi-disciplinary process
Classification of drug metabolizing enzymes: towards the development of new chemical entity to
meet the current medical need of various diseases.
Various new techniques such as combinatorial
1. Microsomal (inducible) - Mixed-function oxidases
(Cytochrome P-450 reductase and NADPH), chemistry, molecular modeling and high throughput
Glucuronyl transferase and enzymes involved in screening are used to choose a potential drug for
hydrolysis and oxidation. discovery and development. Majority of the drug
2. Non-microsomal (non-inducible) - All conjugations molecules fails during the drug development process
except glucuronidation. due to its biopharmaceutical properties. The basic
Non-microsomal enzymes metabolize the drugs concept of pharmacokinetic is quantification of
through conjugation, oxidation, reduction and clearance rate, biological half-life, extent of protein
hydrolysis [22-24]. binding and volume of distribution in the biological
matrix of the drug and its metabolites by selective and
Evaluation techniques of drug metabolism: sensitive bioanalytical method. Preliminary screening of
pharmacokinetic properties is essential and have
1. In vitro methods – Assess the biochemical important role in the drug discovery and development.
toxicology, cytotoxicity, irreversible drug protein During the drug development any drug has poor
binding, drug metabolism and enzyme regulation. pharmacokinetic properties it will be excluded from the
further process to fulfill the current medicinal needs.
i. Enzyme system - Enzymes such as cytochrome
P450, CYP1A, CYP2C, CYP2D, CYP2E, CYP3A Reference
and CYP4A.
ii. Subcellular fractions - Microsomes as 1. Lakshmana Prabu S, Thirumurugan R,
subcellular fraction composed of endoplasmic Suriyaprakash TNK, Ruckmani K (2014) The Role of
reticulum and enzymes such as flavin the Drug Discovery, Clinical, and Regulatory Affairs
monomoxygenases, glucuronyltransferase, Teams in Turning a Potent Agent into a Registered
Product. In: Elsevier Reference Module in

Lakshmana Prabu S and Suriyaprakash TNK. Basics of Biopharmaceutics: Copyright© Lakshmana Prabu S and Suriyaprakash TNK.
A Mini Review. Bioequiv & Bioavailab Int J 2017, 1(1): 000103.
4
Bioequivalence & Bioavailability International Journal

Chemistry, Molecular Sciences and Chemical 15. Nicolazzo JA, Finnin BC (2008) In vivo and in vitro
Engineering, Reedijk J. (Ed.) Elsevier, Waltham, MA. models for assessing drug absorption across the
buccal mucosa. Drug Absorption Studies 7: 89-111.
2. Pharmaceutical Research and Manufacturers of
America (PhRMA), Pharma FAX of the Week, May 2, 16. Hubatsch I, Ragnarsson EGE, Artursson P (2007)
2003, R&D Process: Long, Expensive, Risky Road. Determination of drug permeability and prediction
of drug absorption in Caco-2 monolayers. Nat
3. Pliska V, Testa B, Van de Waterbeemd H (1996) Protocols 2(9): 2111-2119.
Lipophilicity in Drug Action and Toxicology. VCH,
Weinheim J Med Chem 39(26): 5287-5288. 17. Quan Y, Jin Y, Faria TN, Tilford CA, He A, et al.
(2012) Expression Profile of Drug and Nutrient
4. Smith DA, Allerton C, Kalgutkar, Waterbeemed H, Absorption Related Genes in Madin-Darby Canine
Walker DK, et al. (2012) In: Pharmacokinetics and Kidney (MDCK) Cells Grown under Differentiation
Metabolism in Drug Design. Phytochemistry 51. Conditions. Pharmaceutics 4(2): 314-333.
5. Mehrotra N, Gupta M, Kovar A, Meibohm B (2007) 18. Habucky K (2005) Methods to assess absorption in
the role of pharmacokinetics and drug discovery, In: Pharmacokinetics Regulatory-
pharmacodynamics in phosphodiesterase-5 Industrial-Academic Perspective. Welling PG and
inhibitor therapy. Int J Impot Res 19: 253-264. Tse FLS (Ed.), Marcel Dekker, NY67: 21-37.
6. Panchagnula R, Thomas NS (2000) 19. Smith DA, van de Waterbeemd H, Walker DK,
Biopharmaceutics and pharmacokinetics in drug Mannhold R, Kubinyi H, et al. (2001) In:
research. Int J Pharmaceutics 201: 131-150. Pharmacokinetics and Metabolism in Drug Design.,
Timmerman H (Ed.), Wiley-VCH Verlag GmbH,
7. Lin JH, Lu AY (1997) Role of Pharmacokinetics and Weinheim 51: 47-57.
Metabolism in Drug Discovery and Development.
Pharmacol Rev 49(4): 403-449. 20. Kari A, Sateesh G, Suresh B, Rao BSS (2012) Factors
Effecting on Drug Distribution. The pharma
8. Gunaratna C (2000) Drug metabolism and innovation 1(6): 69-73.
pharmacokinetics in drug discovery: a primer for
bioanalytical chemists, part I. Current 21. Blomhoj M, Kjeldsen TH, Ottesen J (2014)
separation 19: 17-23. Compartment models. Pp: 1-47.

9. Lakshmana Prabu S, Suriya Prakash TNK (2012) 22. Smith DA, van de Waterbeemd H, Walker DK,
Extraction of Drug from the biological matrix: A Mannhold R, Kubinyi H, et al.(2001). In:
review. In: Applied biological engineering Pharmacokinetics and Metabolism in Drug Design.
principles and practice. Naik GR (Eds.), InTech, (Ed.), Biotransformation of drugs. Wiley-VCH
Croatia, 479-506. Verlag GmbH, Weinheim, pp. 75-98.
10. Ali AS, Abdel-Rahman MS, Rahman F, Osman OH 23. Handschin C, Meyer UA (2003) Induction of drug
(2013) Basic Principles of Therapeutic Drug metabolism: the role of nuclear factors. Pharmacol
Monitoring. J Appl Biopharm Pharmacokinet 1: 87- Rev 55(4): 649–673.
95.
24. Benet LZ, Oie S, Schwartz JB (1995). In: Goodman
11. Satoskar RS, Bhandarkar SD, Nimala NR (1993) In: and Gillman’s The Pharmacological Basis for
Pharmacology and Pharmacotherapeutics. (ed.), Therapeutics, McGraw-Hill, New York, pp: 1707–
Popular Prakashan Private Ltd, Mumbai, pp: 1-50. 1792.

12. http://www.us.elsevierhealth.com/media/us/samp 25. Hayes RH, Pool WF, Sinz MW, Woolf TF (2005)
lechapters/9781416066279/Chapter %2002.pdf Recent developments in drug metabolism
[Accessed on 10.05.2017]. methodology. In: Pharmacokinetics Regulatory-
Industrial-Academic Perspective. Welling PG, Tse
13. Levine RR. (2000) Pharmacology: Drug Actions and FLS, Marcel Dekker, NY, 67: 201-234.
Reactions, 6th (edn.) New York, Parthenon.
26. Lakshmana Prabu S, Suriya Prakash TNK, Ruckmani
14. Brahmankar DM, Jaiswal SB, Vallabh prakashan K, Thirumurugan R. (2015) Biopharmaceutics and
(1995) In: Biopharmaceutics and pharmacokinetics pharmacokinetics. In: Basic Pharmacokinetic
a treatise. Absorption of drugs. New Delhi, pp: 5-75. Concepts and Some Clinical Applications. Ahmed
TA.

Lakshmana Prabu S and Suriyaprakash TNK. Basics of Biopharmaceutics: Copyright© Lakshmana Prabu S and Suriyaprakash TNK.
A Mini Review. Bioequiv & Bioavailab Int J 2017, 1(1): 000103.
5
Bioequivalence & Bioavailability International Journal

27. Smith DA, van de Waterbeemd H, Walker DK, 29. Brown D, Tomlin M (2010) Pharmacokinetic
Mannhold R, Kubinyi H et al. (2001) In: Principles. In: Pharmacology and pharmacokinetics
Pharmacokinetics and Metabolism in Drug Design., A Basic reader. Tomlin M (ed.) Springer-Verlag
pp. 59-66. London Limited, pp. 13-52.

28. Smith DA, van de Waterbeemd H, Walker DK, 30. Tracy TS. Metabolism and excretion of drugs. pp.
Mannhold R, Kubinyi H, (2001) In: 34-47.
Pharmacokinetics and Metabolism in Drug Design.,
Weinheim, enal clearance. pp. 67-74.

Lakshmana Prabu S and Suriyaprakash TNK. Basics of Biopharmaceutics: Copyright© Lakshmana Prabu S and Suriyaprakash TNK.
A Mini Review. Bioequiv & Bioavailab Int J 2017, 1(1): 000103.