The Influence of Physicochemical Properties on ADME Iain Martin Iain Martin; Physchem Forum 2 1
Physchem and ADME A quick tour of the influence of physicochemical properties on: Absorption Distribution Metabolism Excretion Iain Martin; Physchem Forum 2 2
Absorption: solubility & permeability Aqueous solubility is a prerequisite for absorption Aqueous solubility and membrane permeability tend to work in opposite directions aq. solubility permeability Therefore, a balance of physicochemical properties is required to give optimal absorption Iain Martin; Physchem Forum 2 3
Absorption: solubility & permeability Lipinski (2000) J. Pharmacol. Toxicol. Meth., 44, p235 Iain Martin; Physchem Forum 2 4
Absorption: permeability Transcellular (Passive diffusion) Concentration gradient (Fick s law) Lipid solubility Degree of ionisation ydrogen bonding Size/shape. Paracellular (passage through cell junctions and aqueous channels) Active transport Iain Martin; Physchem Forum 2 5
Permeability: Caco2 assay 2 1.5 y = -0.2183x 2 + 0.8639x + 0.4508 R 2 = 0.5362 Riley et al., (2002) Current Drug Metabolism, 3, p527 1 Log P app 0.5 0-1 0 1 2 3 4 5-0.5 clogd 7.4 Strong relationship between permeability and logd Iain Martin; Physchem Forum 2 6
Permeability: Caco2 assay eutral Basic P app LogP Issues of Solubility and membrane retention Iain Martin; Physchem Forum 2 7
Absorption - ionisation The central principle is that only unionised (neutral) form of drugs will cross a membrane Gut lumen + + A - A Blood stream A + + A - Blood flow Absorption Absorption Iain Martin; Physchem Forum 2 8
Absorption - ionisation In man, stomach is ~ p 2 and small intestine ~ p 6 (weak) ACIDS Unionised form is more prevalent in the stomach. Although some absorption of acids takes place in the stomach, absorption also occurs in small intestine due to: Very large surface area (600x cylinder) Removal of cpd by PPB & blood flow Ionisation of cpd in blood shifts equilibrium in favour of absorption (weak) BASES Unionised form is more prevalent in the small intestine. Bases are well absorbed from small intestine Very large surface area Removal of cpd by blood flow Ionisation equilibrium is countered by distributional factors Iain Martin; Physchem Forum 2 9
Iain Martin; Physchem Forum 2 10 Absorption -bonding Absorption -bonding Diffusion through a lipid membrane is facilitated by shedding -bonded water molecules The higher the -bonding capacity, the more energeticallyunfavourable this becomes 2 2 2
Absorption: PSA The hydrogen-bonding potential of a drug may be expressed as Polar Surface Area (PSA) Polar surface area is defined as a sum of surfaces of polar atoms (usually oxygens, nitrogens) and their attached hydrogens Frequency 250 200 150 100 non-cs CS Distribution of Polar Surface Area for orally administered CS (n=775) and non-cs (n=1556) drugs that have reached at least Phase II efficacy trials. After Kelder et al., (1999) Pharmaceutical Research, 16, 1514 50 0 0 20 40 60 80 100 120 140 160 180 200 220 240 260 Polar Surface Area Iain Martin; Physchem Forum 2 11
ral drug properties Lipinski s Rule of 5 : Poor absorption is more likely when: Log P is greater than 5, Molecular weight is greater than 500, There are more than 5 hydrogen bond donors, There are more than 10 hydrogen bond acceptors. Together, these parameters are descriptive of solubility Iain Martin; Physchem Forum 2 12
ral drug properties Molecular weight and lipophilicity 25 10 count % 20 15 10 5 pdr99 count % 5 PDR99 0 100 200 300 400 500 600 700 800 900 Mwt 0-5 -2.5 0 2.5 5 7.5 10 ACDlogP Iain Martin; Physchem Forum 2 13
ral drug properties ydrogen bonding count % 40 35 30 25 20 15 10 5 0 0 4 8 12 16 20 Acceptors PDR99 count % 35 30 25 20 15 10 5 0 0 2 4 6 8 10 Donors PDR99 The number of rotatable bonds (molecular flexibility) may also be important.. Iain Martin; Physchem Forum 2 14
ral drug properties Mol. Wt. PSA BA BD Rot. Bond clogp 95 th (5 th ) percentile on-cs CS 611 449 127 73 9 5 5 3 14 9 6.2 (-1.2) 5.7 (0.4) In general, CS drugs are smaller, have less rotatable bonds and occupy a narrower range of lipophilicities. They are also characterised by lower -bonding capacity Iain Martin; Physchem Forum 2 15
Are Leads different from Drugs? prea et al., (2001). Property distribution analysis of leads and drugs. Mean increase in properties going from Lead to Drug MW AC RTB D clogp clogd Mean 89 1.0 2.0 0.2 1.16 0.97 If, as a result of Lead ptimisation, our compounds become bigger and more lipophilic, we need to make sure that we start from Lead- Like properties rather than Drug-Like properties Iain Martin; Physchem Forum 2 16
Distribution: Plasma and Tissue binding The extent of a drug s distribution into a particular tissue depends on its affinity for that tissue relative to blood/plasma It can be thought of as whole body chromatography with the tissues as the stationary phase and the blood as the mobile phase Drugs which have high tissue affinity relative to plasma will be retained in tissue (extensive distribution) Drugs which have high affinity for blood components will have limited distribution Iain Martin; Physchem Forum 2 17
Distribution: Plasma and Tissue binding The major plasma protein is albumin (35-50 g/l) which contains lipophilic a.a. residues as well as being rich in lysine There is a trend of increasing binding to albumin with increasing lipophilicity. In addition, acidic drugs tend to be more highly bound due to charge-charge interaction with lysine R1 R2 A + + A - 3 + Bases also interact with alpha1-acid gp (0.4-1.0 g/l) Iain Martin; Physchem Forum 2 18
Plasma and Tissue binding (p 7.4) Tissue cell membranes contain negatively-charged phospholipid Bases tend to have affinity for tissues due to charge-charge interaction with phosphate head-group Acids tend not to have any tissue affinity due to chargecharge repulsion with phosphate head-group R 3 + R Iain Martin; Physchem Forum 2 19
Distribution - V ss What effect does plasma and tissue binding have on the values of V SS that we observe? VSS = Vp + (V T. fu fu P T ) V p = physiological volume of plasma V T = physiological volume of tissue(s) fu p = fraction unbound in plasma fu T = fraction unbound in tissue(s) Iain Martin; Physchem Forum 2 20
Distribution - V ss VSS = Vp + (V T fu. fu P T ) Acids tend to be highly plasma protein bound; hence fu P is small Acids have low tissue affinity due to charge repulsion; hence fu T is large Acids therefore tend to have low V SS (< 0.5 L/kg) Vss Vss (L/kg) (L/kg) Clinically-used Clinically-used Drugs Drugs 100 100 Acid Acid 10 10 1 1 0.1 0.1 0.01 0.01-2 -2-1 -1 0 0 1 1 2 2 3 3 4 4 5 5 LogD LogD Iain Martin; Physchem Forum 2 21
Distribution - V ss VSS = Vp + (V T fu. fu P T ) eutrals have affinity for both plasma protein and tissue Affinity for both is governed by lipophilicity Changes in logd tend to result in similar changes (in direction at least) to both fu P and fu T eutrals tend to have moderate V SS (0.5 5 L/kg) Vss Vss (L/kg) (L/kg) Clinically-used Clinically-used Drugs Drugs 100 100 eutral eutral 10 10 1 1 0.1 0.1 0.01 0.01-2 -2-1 -1 0 0 1 1 2 2 3 3 4 4 5 5 LogD LogD Iain Martin; Physchem Forum 2 22
Distribution - V ss VSS = Vp + (V T fu. fu P T ) Bases have higher affinity for tissue due to charge attraction fu P tends to be (much) larger than fu T Vss Vss (L/kg) (L/kg) 100 100 10 10 1 1 Clinically-used Clinically-used Drugs Drugs Base Base Bases tend to have high V SS (>3 L/kg) 0.1 0.1-2 -2-1 -1 0 0 1 1 2 2 3 3 4 4 5 5 LogD LogD Iain Martin; Physchem Forum 2 23
Distribution - V ss VSS = Vp + (V T fu. fu P T ) Clinically-used Clinically-used Drugs Drugs 100 100 10 10 Acid Acid Base Base eutral eutral Vss (L/kg) Vss (L/kg) 1 1 0.1 0.1 0.01 0.01-2 -2-1 -1 0 0 1 1 2 2 3 3 4 4 5 5 LogD LogD Iain Martin; Physchem Forum 2 24
Distribution effect of p Distribution Ion trapping of basic compounds Distribution/Excretion Aspirin overdose & salicylate poisoning Iain Martin; Physchem Forum 2 25
Distribution: Ion trapping Ion trapping can occur when a drug distributes between physiological compartments of differing p The equilibrium between ionised and unionised drug will be different in each compartment Since only unionised drug can cross biological membranes, a drug may be trapped in the compartment in which the ionised form is more predominant Ion trapping is mainly a phenomenon of basic drugs since they tend to distribute more extensively and. The cytosolic p of metabolically active organs tends to be lower than that of plasma, typically p 7.2 Iain Martin; Physchem Forum 2 26
Distribution: Ion trapping Ion trapping of a weak base pka 8.5 Plasma p 7.4 Membrane Cytosol p 7.2 7.4 B B 4.8 B+ 92.6 B+ 95.2 Distribution Distribution Iain Martin; Physchem Forum 2 27
Ion trapping: lysosomes Lysosomes are membrane-enclosed organelles Contain a range of hydrolytic enzymes responsible for autophagic and heterophagic digestion Abundant in Lung, Liver, kidney, spleen with smaller quantities in brain, muscle p maintained at ~5 (4.8). Iain Martin; Physchem Forum 2 28
Ion trapping: lysosomes Ion trapping of a weak base p 8.5 Plasma p 7.4 Membrane Cytosol p 7.2 Membrane Lysosome p 4.8 7.4 B B 4.8 B 0.02 B+ 92.6 B+ 95.2 B+ 99.8 Distribution Distribution Iain Martin; Physchem Forum 2 29
Ion trapping: lysosomes Effect of lysosomal uptake is more profound for dibasics Theoretical lysosome:plasma ratio of ~ 160,000 Apparent volume of liver may be 1000 X physical volume Azithromycin achieves in vivo tissue: plasma ratios of up to 100-fold and is found predominantly in lysosome-rich tissues Erythromycin V SS = 0.5 L/kg Azithromycin V SS = 28 L/kg Iain Martin; Physchem Forum 2 30
Salicylate poisoning Aspirin (acetylsalicylic acid) is metabolised to the active component salicylic acid Due to its acidic nature and extensive ionisation, salicylate does not readily distribute into tissues But after an overdose, sufficient salicylate enters the CS to stimulate the respiratory centre, promoting a reduction in blood C 2 The loss of blood C 2 leads a rise in blood p - respiratory alkalosis Iain Martin; Physchem Forum 2 31
Salicylate poisoning The body responds to the alkalosis by excreting bicarbonate to reduce blood p back to normal In mild cases, blood p returns to normal. owever in severe cases (and in children) blood p can drop too far leading to metabolic acidosis This has further implications on the distribution of salicylate, its toxicity and subsequent treatment Iain Martin; Physchem Forum 2 32
Salicylate poisoning 1 p 7.4 8000 ormal BRAI Bicarbonate BLD 4 p 6.8 8000 Acidosis Acidosis leads to increase in unionised salicylate in the blood, promoting distribution into brain resulting in CS toxicity. This is treated with bicarbonate which increases blood p and promotes redistribution out of the CS. Iain Martin; Physchem Forum 2 33
Salicylate poisoning BLD KIDEY Reabsorption URIE 1 p 6.0 300 Filtration Bicarbonate Unbound fraction of both species is filtered; nly neutral species is reabsorbed Reabsorption 0.01 p 8.0 300 Bicarbonate incrseases urine p leading to significantly decreased reabsorption and hence increased excretion Iain Martin; Physchem Forum 2 34
Metabolism: lipophilicity X Metabolic stability Gluc -1 0 1 2 3 4 logd As a general rule, liability to metabolism increases with increasing lipophilicity. owever, the presence of certain functional groups and SAR of the metabolising enzymes is of high importance Iain Martin; Physchem Forum 2 35
Metabolism vs. Excretion Effect of logd on renal and metabolic clearance for a series of chromone-2-carboxylic acids Clearance (ml/min/kg) 16 14 12 10 8 6 4 2 Renal Metabolic Replotted from Smith et al., (1985) Drug Metabolism Reviews, 16, p365 0-1 -0.5 0 0.5 1 1.5 2 LogD Balance between renal elimination into an aqueous environment and reabsorption through a lipophilic membrane Iain Martin; Physchem Forum 2 36
Renal Excretion Effect of LogD on renal clearance of β-blockers Van de Waterbeemd et al., (2001) J. Med. Chem, 44, p1313 ote that only unbound drug is filtered and that PPB increases with logd Iain Martin; Physchem Forum 2 37
Summary ADME processes are determined by the interaction of drug molecules with: Lipid membranes Plasma and tissue proteins Drug metabolising enzymes Transporters These interactions are governed, to a large extent, by the physicochemical properties of the drug molecules Understanding the influence of these properties is therefore pivotal to understanding ADME and can lead to predictive models In general, good (oral) ADME properties requires a balance of physicochemical properties Lead ptimisation needs physicochemical room to optimise Iain Martin; Physchem Forum 2 38
References & Further Reading MacIntyre and Cutler (1988). The potential role of lysosomes in the tissue distribution of weak bases. Biopharmaceutics and Drug Disposition, 9, 513-526 Proudfoot (2005). The evolution of synthetic oral drug properties. Bioorganic and Medicinal Chemistry Letters 15, 1087-1090 prea et al., (2001) J. Chem. Inf. Comput. Sci. 41, 1308-1315 van de Waterbeemd et al., (2001). Lipophilicity in PK design: methyl, ethyl, futile. Journal of Computer-Aided Molecular Design. 15, 273-86 Wenlock et al., (2003). A comparison of physiochemical property profiles of development and marketed oral drugs. J. Med. Chem. 2003 Iain Martin; Physchem Forum 2 39