USING THE POLARITY CHARACTERISTICS OF A DRUG S FUNCTIONAL GROUPS TO ESTIMATE SOLUBILITY CHARACTERISTICS Lessn Objectives 1. Understand what is meant by lgp; knw the difference between MlgP and ClgP 2. Utilize the plarity f a drug mlecules functinal grups t estimate the water slubility and permeability capacity f that drug mlecule 3. Knw the general limits t lgp fr ability t crss lipid membranes (transitin thrugh varius bilgical cmpartments such as gut and vasculature) 4. Knw the general limits t lgp fr ability t shw sufficient slubility in water 5. Knw hw the limits t membrane permeability can be used t therapeutic advantage, as in the case f Mannitl and Srbitl 6. Understand hw different slubilities are required fr different circumstances, as with the frmatin f prdrug esters f Chlramphenicl with carbxylic acids f differing lipphilicities Lemke Methd Organic Functinal Grups, Intrductin t Medicinal Organic Chemistry, 4 th Ed., T.L. Lemke; Lippenctt, Williams & Wilkens (2003) Fye s Principals f Medicinal Chemistry, 5 th Ed., D.A. Williams & T.L. Lemke; Lippenctt, Williams & Wilkens (2003) a. Fcuses n thse functinalities that can cntribute t increased aqueus slubility and assigns a carbn carry alng value i. This is t say Lemke s view fcuses n slubility decreasing with increased mlecular size and assesses functinal grup cntent t determine whether the influence f increased size (increased Van der Waals frces, decreased entrpy f water) has been ffset b. Inizatin (full dissciatin: strng acid with strng r weak base, strng base with strng r weak acid) cntributes a whpping 20-30 carbn t the estimatin i. Large variatin in the number f carbn s carried shws the difficulty f bth appraches when accurately determining inizatin influence
2. lgp a. Als sums functinal grups, but includes values fr bth lipphilic and hydrphilic functinalities b. Greater the number, the lwer the slubility, since P ctanl/water partitin rati; i.e. the amunt f drug mlecule that disslves in ctanl divided by the amunt that can be disslved in water c. USP defines slubility as > 3.3%, r lgp +.5
Aside fr the values listed fr the nitr grups, the p values in the table abve weigh the values fr varius systems (such as aliphatic vs. armatic). This makes the apprximatin rather crude as the ability fr charge t disperse is very system dependant. Ntice the large psitive value fr intramlecular hydrgen bnding, IMHB =.65, which reflects the imprtance f hydrgen bnding t water fr slubilizatin.
Interpretatin f lgp Values Limits t Slubility Characteristics Bilgical membranes behave as if lipids (plar heads being slvated) As such, bilgical membranes act as barriers t highly plar species (a fully inic species being the upper limit t plarity with regard t individual functinal grups) In rder fr a drug t absrb by the ral rute, it must have sufficient hydrphilic character t disslve sparingly (again nte these are equilibrium prcesses). In rder fr a drug t absrb by the ral rute, it must have sufficient lipphilic character t crss bilgical membranes If drug absrptin is a balance f lipid and water slubility, let s ask the bundary questins
Hw much water slubility is t much? Hw much lipid slubility is t much? Perusing lists f physicchemical prperties fr therapeutic agents, we find (tssing ut values that are likely t be carrier mediated) typical lgp values d nt exceed -4. Sme examples are Mannitl (-4.67), Srbitl (-4.67), Zanamivir (- 3.75), and Tbramycin (-3.44) Mannitl des nt crss the bld brain barrier in fact, it des nt crss any barrier and must be administered IV. It is, hwever, freely filtered by the kidney; this fact cupled t its high smtic tendency makes Mannitl a useful smtic diuretic Srbitl is administered rally, but fr use as a laxative (bear in mind it is used as a sweetener in sme sugarless candies) Fr Tbramycin the stry is the same, IV rute r available by inhalatin fr CF patients with Pneumnia (the primary use fr this aminglycside antibitic) Tbramycin is nt absrbed rally Cnsidering the structural similarity between the aminglycsides (e.g. s Gentamicin, Kanamycin) wuld yu expect any f these cmpunds t be available rally? Ntice that Tbramycin is inizable, but that nly makes the cmpund mre plar we are cnsidering the plarity f uninized species t see if they (1) are water sluble (2) have the ptential fr crssing bilgical membranes Zanamivir (Relenza) is available by inhalatin fr influenza A & B
Oral biavailability = 1-5% What is a ptential plus f this limited ability t crss membranes? (Hint: Tbramycin is at times administered intrathecally r intraventricularly fr CNS infectins) Well, let s try smething in the lgp = -2 t -1 range Ganciclvir (-2.07) Available rally fr CMV infectin but is prly biavailable Biavailability: 5% fasting, 6-9% with meal, 22% with high fat meal Nucleside analg apparently accunts fr high presence in CSF, ca. 40% f plasma levels Oxytetracycline (-1.22) Gd ral availability Tetracyclines still have widespread use, thugh there are many resistant micrbes ut there
Ceftriaxne (-1.76) 3 rd generatin cephalsprin Nt absrbed rally, used fr serius gram neg. infectins Des penetrate int CSF (useful fr meningitis) and crsses the placenta Ceftibuten (-1.06) Als third generatin cephalsprin, with similar prfile t ceftriaxne Rapidly absrbed as capsule r ral suspensin As may be seen by cmparing Ceftrixne t Gancyclvir, the crrelatin f lgp t ral biavailability is nly an apprximatin. T emphasize this pint, 2 ther members f this class are Ceftaxime (-.31) which is nt absrbed rally and nly available as an IV injectin, and Cefixime (-.51) which is available rally, thugh absrptin is slw and incmplete. On the ther end f the spectrum we must ask the questin hw much lipphilicity is t much
The majr cncern fr ral absrptin is disslutin, since undisslved drug mlecules are nt absrbed We d have sme cntrl ver water slubility in mst cases (ca. 90% f drugs have an inizable functinality), since we have the capacity t frm inized mlecules r salts which vastly imprve the ability t interact with water in a mst favrable fashin. Further, the GI tract varies in ph frm 1 8, and s drugs will ptimally disslve accrding t their ph. Nte that the lgp f Phenbarbital is 1.71
Ntice als the y-axis is mg/100min/cm 2. This is t say that surface area f the slid drug surface is imprtant fr disslutin. If we cnsider the abve in terms f absrptin f a drug, ultimately int the bld stream, we shuld be able t see frm the abve that we are balancing disslutin and slubility with membrane permeability fr slid ral dsing. Frm a bipharmaceutics standpint the bilgical absrbing surface is als crucial, s the upper small intestine ends up absrbing a large amunt f drug agents. Again, tssing ut cmpunds that are likely t be carrier mediated (by apprximatin t endgenus cmpunds) we find therapeutic agents generally fall belw 9 2 examples are Amidarne (8.59) and Halfantrine (8.86) Amidarne (8.59) Antiarrhythmic used fr life threatening ventricular arrhythmias Slw and incmplete biavailability frm ral dsing (generally ca. 50%) Peak plasma in 3-7 hrs Steady state plasma levels nt reached until 1-5 mnths f daily therapy Onset f actin 2-3 mnths Huge vlume f distributin 70 L/kg, Huge eliminatin half-life with persistence f side effects
Halfantrine (8.86) Synthetic antimalarial related t meflquine and quinine Absrptin is pr and widely varied n an empty stmach but is increased ca. 10x with a high fat meal Why? It shuld be nted that with the abve examples that increased biavailability with fd are cntrary t the usual case f decreased absrptin (lwer AUC) r decreased Cp max Let s lk at a few cmpunds that have mre usual values (ntice that the barbituric acid cre structure helps t cntrl fr sme f the anmalus differences that might be experienced when cmparing highly varied structures f differing lgp values) Again, aside frm erratic absrptin with high lgp cmpunds, they als tend t sequester int fatty tissues, thus resulting in very high vlumes f distributin and lng half lives. Just s yu knw (believe me, yu will cmmit this relatinship t memry eventually but nt fr this test) t 1/2 = (.7 x V D )/Cl, where the systemic clearance, Cl, is the fractin f the distributin vlume cleared f drug per unit time (fr drugs which are cleared by metablism in the liver, the clearance cannt exceed the hepatic bld flw f 1.25L/min) The fllwing table and graph prvides evidence fr absrptin fllwing lgp acrss a series f cmpunds (with similar pk a s)
Nte the abve is fr chlrfrm/water as the partitining system. The values fr ctanl/water lgp are Secbarbital 2.33 Phenbarbital 1.71 The relative ranking is the same
The abve crrelatin shuld help drive hme the idea that drug absrptin is a balancing act between aqueus slubility and membrane permeability. In fact, this is the real pwer f lgp determinatins, since we are referring t a partitining between lipid and water that relates well t what we are trying t accmplish achieve a therapeutic cncentratin f drug in plasma. While lgp is reflective f water slubility, it is a better indicatin f this critical partitining relatinship. The fllwing shuld clarify The greater the plarity f the drug mlecule, the greater the slubility in the highly plar aqueus envirnment (like disslves like). Plarity is described by lgp values, which expresses the rati f partitining between ctanl and water in expnential terms Since the lgp partitin rati is defined as ctanl ver water lgp = (lg) the higher the number, the greater the lipid slubility, r lipphilicity, r hydrphbicity. Cnversely, the higher the negative value, the greater the aqueus slubility, r hydrphilicity, r lypphbicity This is a lg scale. MlgP = 0 indicates equal partitining between ctanl and water. A MlgP = 2 between 2 structures indicates a 100x greater partitining int ctanl fr the secnd structure. Similarly, MlgP = -2 indicates a 100x greater partitining int water. Partitining is reflective* f H 2 O slubility. As an example, let s cnsider an apprximatin using ClgP values (ACD Slaris V4.67) between Celecxib and Rfecxib Celecxib, ClgP = 3.01 H 2 0 slubility =.007 mg/ml 1-ctanl slubility = 7.87 mg/ml 7.87/.007 = 1124, MlgP = 3.05 Rfecxib ClgP = 1.63 H 2 0 slubility =.009 mg/ml 1-ctanl slubility =.117 mg/ml.117/.009 = 13, Mlg13 = 1.11 1124/13 = 86.5, Mlg86.5 = 1.94 = 3.05 1.11.007 mg/ml =.0007% (w/v%) slubility.009 mg/ml =.0009% (w/v%) slubility.009/.007 = 1.28, Mlg1.28 =.107 Clearly.107 des nt crrespnd well t the difference in lgp values (ntice that the slight increase in water slubility fr Rfecxib is accmpanied by a tremendus lss in ctanl slubility)
Returning t slubility cnsideratins, we must als cnsider hw we wish t be able t deliver a drug when cnsidering ptimal slubility characteristics Let s use chlramphenicl (lgp = 1.02) as an example Brad spectrum antibitic with reasnable penetratin int the CNS (imprtant as an alternative treatment fr Meningitis) Reserved fr treatment f serius infectins resistant t penicillin G and ampicillin wing t serius txicities (bld dyscrasias, bne marrw depressin) LgP <.5 (3.3% H 2 O slubility) is generally taken t mean water sluble Chlramphenicl LgP >.5, but still enugh slubility fr bitter taste t cme thrugh enter palmitate ester as prdrug
Hwever, Chlramphenicl is als used in settings where IV administratin is imprtant. Here, we wuld like t increase the water slubility such that there is n chance f precipitating ut a lipphilic species &/r decrease the amunt f material that needs t be injected