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Drug transport model in Advance Biopharmaceutics

Drug transport model in Advance advance biopharmaceutics

Science◦
Guided by: Dr. J. S. Patil Associate Professor Dept. of IPQA Presenter: Mr. Rushikesh R. Bharati Roll No. MIP01 M. Pharm 1st Year SEMINAR PRESENTATION R. C. PATEL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH, SHIRPUR. DRUG TRANSPORT MODEL 02-05-2025 01
Lipophilicity and drug absorption Henderson Hasselbach equation pH partition theory Tight junction complex Drug solubility and pH Permeability solubility charge state Introduction Content References 02-05-2025 02
 Introduction:-  The drug transport model refers to the process by which drugs are absorbed, distributed, metabolized, and eliminated (ADME) by the body.  This model helps understand how drugs move through the body, affecting their efficacy and potential side effects.  Key components: Absorption Distribution Refers to the process by which a drug moves from its site of administration into the bloodstream. It's a crucial step in determining the drug's effectiveness. process by which a drug is transported through the body via the bloodstream to reach its target site of action, tissues, and organs. Metabolism Refers to the process by which the body breaks down and chemically alters drugs. This typically occurs in the liver, where enzymes convert the drug into metabolites. Elimination Refers to the process by which the body removes drugs or their metabolites. This occurs through various routes, including: 02-05-2025 03
 Permeability solubility charge state Fick's first law applied to a membrane shows that passive diffusion of a solute is the product of the diffusivity and the concentration gradient of the solute inside the membrane The membrane/water apparent partition coefficient relates the latter internal gradient to the external bulk water concentration difference between the two solutions separated by the membrane. For an ionizable molecule to permeate by passive diffusion most efficiently, the molecule needs to be in its uncharged form at the membrane surface. This is the essence of the pH partition hypothesis 02-05-2025 04
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 DRUG SOLUBILITY AND PH 1. Drug Solubility:  The absorption of drug requires that molecule be in solution at absorption site.  Dissolution, an important step, depends upon solubility of drug substance. 2. pH solubility profile:  Is a graphical representation of how the solubility of a substance changes as the pH of the solution changes  pH environment of GIT varies from acidic in stomach to slightly alkaline in a small intestine 02-05-2025 06
 TIGHT JUNCTION COMPLEX It explain drug absorption from GIT and its distribution across bio-membranes Drug (>100 Daltons) transported by passive diffusion depend upon dissociation constant, pKa of the drug lipid solubility, pH at absorption site. Tight junctions, also known as occluding junctions The closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. Tight junctions are composed of a branching network of sealing strands, each strand acting independently from the others. Therefore, the efficiency of the junction in preventing ion passage increases exponentially with the number of strands. Each strand is formed from a row of transmembrane proteins. 02-05-2025 07
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 PH PARTITION THEORY • It explain drug absorption from GIT and its distribution across bio-membranes. • Drug (>100 Daltons) transported by passive diffusion depend upon: dissociation constant, pka of the drug, lipid solubility, absorption site. • Most drugs are either weak acids or weak bases whose degree of ionization is depend upon pH of biological fluid. • For a drug to be absorbed, it should be ionized and the unionized portion should be lipid soluble. • The fraction of drug remaining unionised is a function of both Dissociation constant (pka) and pH of solution. 02-05-2025 09
pH-absorption curve for Acidic and basic drugs. Dotted lines:- Curves predicted by pH-partition hypothesis (Only unionized drug absorbed) Bold lines:- The practical curves (less sleep and shifted) The Virtual pH also called as the microclimate pH, Is different from the luminal pH exists at the membrane surface pH-absorption curve for Acidic and basic 02-05-2025 10
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 HENDERSON HASSELBALCH EQUATION For acid, pKa -pH= log [Cu/Ci] For base, pKa-pH=log [Ci/Cu] Ex: Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have > 99% of unionized form so gets absorbed in stomach. Weak base quinine (pKa=8.5) will have very negligible unionization in gastric pH so negligible absorption. Several pro-drugs have been developed which are lipid soluble to overcome poor oral absorption of their parent compounds. 02-05-2025 12
 Influence of drug pKa and GI pH on drug absorption Drug Site of absorption Very weak acid (pKa>8.5) Unionized at all pH value absorb along entire length of GIT Moderately weak acid (pKa 2.5-7.5) Unionized in gastric pH Ionized in intestinal pH Better absorbed from stomach Strong acid (pKa<2.5) Ionized at all pH value Poorly absorbed from GIT Very weak bases (pKa<5) Unionized at all pH value Absorbed along entire length of GIT Moderately weak bases (pKa 5-11) Ionized in gastric pH Unionized in intestinal pH Better absorbed from intestine Strong bases (pKa>11)t Ionized at all pH value Poorly absorbed from GIT 02-05-2025 13
 Lipophilicity and Drug absorption The gastrointestinal cell membrane are essentially lipoidal. Highly lipid soluble drugs are generally absorbed while decidedly lipid insoluble drugs are in general poorly absorbed. • Certain drugs are poorly absorbed after oral administration even though they are largely unionized in the small intestine, low lipid solubility of the uncharged molecule may be the reason. • A guide to the lipophilic nature of a drug is its partition coefficient between a fat like solvent and water or an aqueous buffer. • The critical role of lipid solubility in drug absorption is guiding principle in drug development. Polar molecules such as gentamicin, ceftriaxone, heparin and streptokinase are poorly absorbed after oral administration and must be given by injection. • Lipid soluble drugs with favorable partition coefficient are usually well absorbed after oral administration. The selection of a more lipid soluble compound from a series of research compounds often result in improved pharmacological activity. 02-05-2025 14
References  Ekins, S., Ecker, G.F., Chiba, P. and Swaan, P.W., 2007. Future directions for drug transporter modelling. Xenobiotica, 37(10-11), pp.1152-1170.  Cecchelli, R., Dehouck, B., Descamps, L., Fenart, L., Buée-Scherrer, V., Duhem, C., Lundquist, S., Rentfel, M., Torpier, G. and Dehouck, M.P., 1999. In vitro model for evaluating drug transport across the blood–brain barrier. Advanced drug delivery reviews, 36(2-3), pp.165-178.  Fundamentals of Biopharmaceutics and pharmacokinetics by V.Venkateswarlu,page no:25  Absorption and drug development solubility permeability charge state by Alex Avdeef 02-05-2025 15
THANK YOU 02-05-2025 16