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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 Hydrogen bonding Size/shape …………. • Paracellular (passage through cell junctions and aqueous channels) • Active transport Iain Martin; Physchem Forum 2 5 Permeability: Caco2 assay 2 y = -0.2183x 2 + 0.8639x + 0.4508 R2 = 0.5362 1.5 Riley et al., (2002) Current Drug Metabolism, 3, p527 Log Papp 1 0.5 0 -1 0 1 2 3 4 5 -0.5 clogD7.4 Strong relationship between permeability and logD Iain Martin; Physchem Forum 2 6 Permeability: Caco2 assay Papp Neutral Basic 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 H + + A- Blood stream HA H+ + A- HA Blood flow Absorption Absorption Iain Martin; Physchem Forum 2 8 Absorption - ionisation • In man, stomach is ~ pH 2 and small intestine ~ pH 6 (weak) BASES (weak) ACIDS • Unionised form is more prevalent in the stomach. • Unionised form is more prevalent in the small intestine. • Although some absorption of acids takes place in the stomach, absorption also occurs in small intestine due to: • Bases are well absorbed from small intestine • Very large surface area • Very large surface area (600x cylinder) • Removal of cpd by blood flow • Removal of cpd by PPB & blood flow • Ionisation equilibrium is countered by distributional factors • Ionisation of cpd in blood shifts equilibrium in favour of absorption Iain Martin; Physchem Forum 2 9 Absorption – H-bonding • Diffusion through a lipid membrane is facilitated by “shedding” H-bonded water molecules • The higher the H-bonding capacity, the more energeticallyunfavourable this becomes H H O H N N H H O H N H N N H 10 N N N H H NH N 2 H NN H Iain Martin; Physchem Forum 2 H H O H O N2 NH O N N H H H O H H H H H2N N N H H 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 Distribution of Polar Surface Area for orally administered CNS (n=775) and non-CNS (n=1556) drugs that have reached at least Phase II efficacy trials. After Kelder et 250 non-CNS Frequency 200 CNS 150 al., (1999) Pharmaceutical Research, 16, 1514 100 50 260 240 220 200 180 160 140 120 100 80 60 40 20 0 0 Polar Surface Area Iain Martin; Physchem Forum 2 11 Oral 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 Oral drug properties Molecular weight and lipophilicity 10 10 20 20 15 15 pdr99 pdr99 10 10 55 00 55 PDR99 PDR99 00 100 100 200 200 300 300 400 400 500 500 600 600 700 700 800 800 900 900 -5 -5 Mwt Mwt Iain Martin; Physchem Forum 2 count % % count count % % count 25 25 -2.5 -2.5 00 2.5 2.5 55 ACDlogP ACDlogP 13 7.5 7.5 10 10 Oral drug properties 35 35 40 40 35 35 30 30 25 25 20 20 15 15 10 10 55 00 30 30 PDR99 PDR99 count % % count count % % count Hydrogen bonding 25 25 20 20 PDR99 PDR99 15 15 10 10 55 00 44 88 12 12 16 16 00 20 20 00 Acceptors Acceptors 22 44 66 88 10 10 Donors Donors • The number of rotatable bonds (molecular flexibility) may also be important………….. Iain Martin; Physchem Forum 2 14 Oral drug properties 95th (5th) percentile Non-CNS CNS Mol. Wt. 611 449 PSA 127 73 HBA 9 5 HBD 5 3 Rot. Bond 14 9 6.2 (-1.2) 5.7 (0.4) cLogP • In general, CNS drugs are smaller, have less rotatable bonds and occupy a narrower range of lipophilicities. They are also characterised by lower H-bonding capacity Iain Martin; Physchem Forum 2 15 Are Leads different from Drugs? • Oprea et al., (2001). Property distribution analysis of leads and drugs. • Mean increase in properties going from Lead to Drug ∆MW Mean • 89 ∆HAC 1.0 ∆RTB 2.0 ∆HDO ∆cLogP 0.2 1.16 ∆cLogD 0.97 If, as a result of Lead “Optimisation”, our compounds become bigger and more lipophilic, we need to make sure that we start from LeadLike 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 O H N R1 R2 N H O HA H + + A+ NH3 • Bases also interact with alpha1-acid gp (0.4-1.0 g/L) Iain Martin; Physchem Forum 2 18 Plasma and Tissue binding (pH 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 NH3 O R O Iain Martin; Physchem Forum 2 19 Distribution - Vss • What effect does plasma and tissue binding have on the values of VSS that we observe? VSS fuP = Vp + ( VT. ) fu T Vp = physiological volume of plasma VT = physiological volume of tissue(s) fup = fraction unbound in plasma fuT = fraction unbound in tissue(s) Iain Martin; Physchem Forum 2 20 Distribution - Vss VSS • Acids tend to be highly plasma protein bound; hence fuP is small • Acids therefore tend to have low VSS (< 0.5 L/kg) Iain Martin; Physchem Forum 2 21 Clinically-used Clinically-usedDrugs Drugs 100 100 Vss(L/kg) (L/kg) Vss • Acids have low tissue affinity due to charge repulsion; hence fuT is large fuP = Vp + ( VT. ) fuT Acid Acid 10 10 11 0.1 0.1 0.01 0.01 -2-2 -1-1 00 11 22 LogD LogD 33 44 55 Distribution - Vss VSS • Neutrals have affinity for both plasma protein and tissue • Changes in logD tend to result in similar changes (in direction at least) to both fuP and fuT • Neutrals tend to have moderate VSS (0.5 – 5 L/kg) Iain Martin; Physchem Forum 2 22 Clinically-used Clinically-usedDrugs Drugs 100 100 Vss(L/kg) (L/kg) Vss • Affinity for both is governed by lipophilicity fuP = Vp + ( VT. ) fuT Neutral Neutral 10 10 11 0.1 0.1 0.01 0.01 -2-2 -1-1 00 11 22 LogD LogD 33 44 55 Distribution - Vss VSS • Bases have higher affinity for tissue due to charge attraction • Bases tend to have high VSS (>3 L/kg) Iain Martin; Physchem Forum 2 23 Clinically-used Clinically-usedDrugs Drugs 100 100 Vss(L/kg) (L/kg) Vss • fuP tends to be (much) larger than fuT fuP = Vp + ( VT. ) fuT Base Base 10 10 11 0.1 0.1 -2-2 -1-1 00 11 22 LogD LogD 33 44 55 Distribution - Vss VSS fuP = Vp + ( VT. ) fuT Clinically-used Clinically-usedDrugs Drugs 100 100 Vss (L/kg) Vss (L/kg) 10 10 Acid Acid Base Base Neutral Neutral 11 0.1 0.1 0.01 0.01 -2-2 Iain Martin; Physchem Forum 2 -1-1 00 24 11 22 LogD LogD 33 44 55 Distribution – effect of pH • 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 pH • 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 pH of metabolically active organs tends to be lower than that of plasma, typically pH 7.2 Iain Martin; Physchem Forum 2 26 Distribution: Ion trapping • Ion trapping of a weak base pKa 8.5 Plasma pH 7.4 7.4 B 92.6 BH+ Membrane B 4.8 BH+ 95.2 Distribution Distribution Iain Martin; Physchem Forum 2 Cytosol pH 7.2 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 • pH maintained at ~5 (4.8). Iain Martin; Physchem Forum 2 28 Ion trapping: lysosomes • Ion trapping of a weak base pH 8.5 Plasma pH 7.4 7.4 92.6 Membrane B BH+ Cytosol pH 7.2 B 4.8 BH+ 95.2 Distribution Distribution Iain Martin; Physchem Forum 2 29 Membrane Lysosome pH 4.8 B 0.02 BH+ 99.8 Ion trapping: lysosomes OH • • • • Effect of lysosomal uptake is more profound for dibasics HO O O O O HO HO OO Theoretical lysosome:plasma ratio of ~ 160,000 N O HO O Erythromycin VSS = 0.5 L/kg Apparent volume of liver may be 1000 X physical volume N Azithromycin achieves in vivo tissue: plasma ratios of up to 100-fold and is found predominantly in lysosome-rich tissues OH HO OH N HO O O O O O O O OH Azithromycin VSS = 28 L/kg Iain Martin; Physchem Forum 2 30 Salicylate poisoning O O OH OH OH O O • 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 CNS to stimulate the respiratory centre, promoting a reduction in blood CO2 • The loss of blood CO2 leads a rise in blood pH - respiratory alkalosis Iain Martin; Physchem Forum 2 31 Salicylate poisoning • The body responds to the alkalosis by excreting bicarbonate to reduce blood pH back to normal • In mild cases, blood pH returns to normal. However in severe cases (and in children) blood pH 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 pH 7.4 OH OH OH O O O 4 pH 6.8 8000 Bicarbonate BRAIN Normal 8000 BLOOD Acidosis • Acidosis leads to increase in unionised salicylate in the blood, promoting distribution into brain resulting in CNS toxicity. • This is treated with bicarbonate which increases blood pH and promotes redistribution out of the CNS. Iain Martin; Physchem Forum 2 33 Salicylate poisoning KIDNEY BLOOD Reabsorption O Unbound fraction of both species is filtered; Only neutral species is reabsorbed pH 6.0 OH OH OH 1 O Filtration OH O O Reabsorption 0.01 300 Bicarbonate OH URINE pH 8.0 OH O O 300 • Bicarbonate incrseases urine pH leading to significantly decreased reabsorption and hence increased excretion Iain Martin; Physchem Forum 2 34 Metabolism: lipophilicity OH X N Metabolic stability N OH NH OGluc N -1 0 1 2 3 4 logD As a general rule, liability to metabolism increases with increasing lipophilicity. However, 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 16 Clearance (ml/min/kg) Replotted from Smith et al., (1985) Drug Metabolism Reviews, 16, p365 Renal 14 Metabolic 12 10 8 6 4 2 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 • Note 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 Optimisation 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, 513526 • Proudfoot (2005). The evolution of synthetic oral drug properties. Bioorganic and Medicinal Chemistry Letters 15, 1087-1090 • Oprea 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