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Chapter 32. Pharmaceutics, Pharmacokinetics and Biopharmaceutics
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Chapter 32.
Phannaceutics, Pharmacokinetics and Biophannaceutics Edward R. G a r r e t t and Oscar E. Araujo College of Pharmacy, University of Florida, Gainesville, FL 32601
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Introduction The a v a i l a b i l i t y of t h e drug from t h e dosage form depends on physical chemical f a c t o r s , chemical i n t e r a c t i o n s and a p r i o r i p r e d i c t i o n s and confirmations of r e l e a s e i n b i o l o g i c a l systems.
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Drug Dissolution and Diffusion The importance of t h e r e l a t i o n s h i p between drug absorption and t h e r a t e processes of d i f f u s i o n and d i s s o l u t i o n has been w e l l established i n recent years. W. Higuchil has reviewed t h e lite r a t u r e and extracted t h e physical and mathematical treatments of drug transport. He considered t h e laws governing t h e d i s s o l u t i o n r a t e s of solids a s affected by a g i t a t i o n , p a r t i c l e s i z e , i n t e r a c t i o n with s o l u t i o n a d d i t i v e s and drug r e l e a s e r a t e s from matrices t h a t do and do not obey Fick's law. The d i f f u s i o n r a t e s of pentobarbital, s a l i c y l i c acid and urea across t h e i s o l a t e d r a b b i t mesentery i n d i c a t e d i f f u s i o n of both i o n i c and non-ionic forms of t h e drugs across t h e membrane. with no s i g n i f i c a n t change i n r a t e due t o pH2. Drug t r a n s p o r t through nonpolar l i q u i d s a s models of l i v i n g membranes indicated t h a t when t h e Hildebrand 6 value of t h e drug molecule apprcached t h a t of t h e l i p o i d a l b a r r i e r , t r a n s er of t h e drug molecule across and through t h e l i p o i d a l b a r r i e r was faster When aqueous d i f f u s i o n a l b a r r i e r s on each s i d e of t h e l i p o i d a l membrane a r e included, Fick's law does n o t f u l l y hold i n t h i s case of protonation of weak bases4. The t r a n s f e r of amidopyrine and s a l i c y l i c acid through an organic l i q u i d obeys t h e t h e o r e t i c a l equation proposed5. The formation of complexes can modify t h e r a t e of t r a n s f e r of drugs t rough such b a r r i e r s and demand modification of t h e d i f f u s i o n a l equations When micron-sized emulsion d r o p l e t s a c t as sinks f o r drug, equations were derived for m i c e l l a r s o l u b i l i z a t i o n t o t a k e i n t o account t h e possible e f f e c t s of an e l e c t r i c a l b a r r i e r between t h e micelle and t h e charged oil-water i n t e r f a c e .? Drug r e l e a s e from water i n o i l emulsions a s a function of pH i n t o an aqueous sink8 and with a separating membrane9 was studied and t h e experimental data agreed with the physical models suggested. I n order f o r i n v i t r o d i s s o l u t i o n s t u d i e s of poorly soluble drugs t o bear any r e l a t i o n s h i p t o & vivo observations, s i n k conditions must be maintained and t h i s can be s i m ulated by t h e presence of an organic solvent phaselo. The k i n e t i c s of simultaneous determinations of v i t r o drug d i s s o l u t i o n and p a r t i t i o n i n g r a t e s i n a s i n g l e system has been studied, a s affected by a g i t a t i o n and temperatwell. The e f f e c t of d i f f e r e n t polymorphic forms on t h e rate of d i s s o l u t i o n and subsequent absorption of a drug has been s h m t o be of extreme importance before recent governmental committees. Suspensions cont a i n i n g only chloramphenicol polymorph B gave s i g n i f i c a n t l y higher blood l e v e l s than suspensions containing only polymorph A, r e g a r d l e s s of p a r t i c l e
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sizel2. The r a t e s of reversion of t h e metastable t o t h e s t a b l e f o n s duri n g d i s s o l u t i o n were c o r r e l a t e d t o t h e c r y s t a l growth r a t e s f o r polymorphs of s u l f a t h i a z o l e and methylprednisolone13. Solvents have a d i s t i n c t influence on t h e shape of c E s t a l s and can promote t h e formation of unstable polymorphic modifications
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P a r t i c l e s i z e has a decided e f f e c t on t h e r a t e of d i s s o l u t i o n of drugs. Examples of t h e i n t e r r e l a t i o n of p a r t i c l e s i z e , s o l u b i l i t y , absorption and t h e r a p e u t i c a c t i v i t y i l l u s t r a t e t h e i r importance i n medicin a l s f o r o r a l , t o p i c a l or p a r e n t e r a l administrationl5. The angle of repose and s l i d i n g angles of sodium borate and b o r i c a c i d powders were calcul a t e d and it was found t h a t t h e cohesive f o r c e between t h e p a r t i c l e s i s n e g l i g i b l y small f o r p a r t i c l e diameters l a r g e r than t h e c r i t i c a l while it s i g n i f i c a n t l y influences t h e angle a t smaller diameterslg:ZeThe apparent s p e c i f i c volume of samples i n t h e l o o s e s t packing i s n e a r l y cons t a n t f o r sizes above t h e c r i t i c a l diameter, b u t it i n c r e a s e s gradually The an l e s with decreasing p a r t i c l e s i z e below t h e c r i t i c a l diameter1?. of repose were a p a r e n t l y lowered by t h e a d d i t i o n of t h e lubricantsl!. The Coulter counter 15 was used t o study t h e p a r t i c l e s i z e d i s t r i b u t i o n of vari o u s samples of griseofulvin. The considerable d i f f e r e n c e s which would a f f e c t s p e c i f i c s u r f a c e area and thus blood l e v e l s demanded s t r i c t e r o f f i c i a l specifications20. Dissolution test procedures which have not been c a l i b r a t e d on t h e b a s i s of i n vivo measurements a r e u n l i k e l y t o r e f l e c t t h e g a s t r o - i n t e s t i n a l absorption and may i n f a c t y i e l d misleading dataz1. I n t r i n s i c dissolution r a t e s varied con i d e r a b l y among t a b l e t s f o r aspirin22, sodium s a l i c y l a t e 2 3 and phenindione2', depending on t h e c r y s t a l l i n e form, compression and tabl e t technology. A new d i s s o l u t i o n apparatus permits 20 d i s s o l u t i o n t e s t s simultaneously and t h e r e s u l t s agree w e l l with standard procedures*S.
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Drug I n t e r a c t i o n s The f i r s t order r a t e s of deaggregation abbetted by wett i n g and d i s p e r s i n g agents of a suspension o f a s u b s t i t u t e benzoic acid and i t s sodium s a l t c o r r e l a t e with t h e r a t e s of solution2 The t h e o r e t i c a l simultaneous r e l e a s e o f a mixture of two non-interacting drugs d i s persed i n an i n e r t p l a s t i c matrix was confirmed by s t u d i e s on a s a l i c y l i c acid-benzoic a c i d p l a s t i c mixture27. The v a l i d i t y of t h e model f o r t h e int e r a c t i n g system, benzocaine-caffeine, was also verified28. Surprisingly, t h e r e l e a s e of s a l i c y l i c a c i d from polyethylene matrices exhibited no r a t e i n c r e a s e i n t h e presence of increasing concentrations of d i b a s i c potassium phosphate even though t h e s o l u b i l i t y increased a s much a s 45 fold. The presence of a s u r f a c t a n t , however, produced a dramatic r a t e increase. The r e s u l t indicated t h a t matrix permeability and r a t e s of permeation by t h e solvent can r e s t r i c t drug r e l e a s e r a t e s a s a function of pore s i z e d i s t r i bution of t h e matrix and wetting p r o p e r t i e s of t h e solvent defined by surf a c e tension and contact angle29. The r e l e a s e of benzoic a c i d and salicyl i c acid i n t o aqueous media from wax matrices a r e b e s t analyzed from a d i f f u s i o n c o n t r o l l e d model and square r o o t of t i m e r e l e a s e profiles30. Over one range of composition t h e r a t e of r e l e a s e of a hydrogenated c a s t o r o i l propylene glycol monostearate-sulfanilamide i s d i f f u s i o n controlled, with high t o f t n o s i t y values. A t higher sulfanilamide concentrations i n t h e tabl e t . t h e r e l e a s e i s not d i f f u s i o n controlled31. Dissolution r a t e s of
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hexestrol, d i e n e s t r o l and griseofulvin increased s i g n i f i c a n t l y i n t h e presence of l y ~ o l e c i t h i n 3a ~s they did f o r t e s t o s t e r o n e i n aqueous s o l u t i o n s of polysorbates33. I n general, increasing conc n t r a t i o n s of surface-active agents increase t h e d i s s o l u t i o n r a t e s of drugs3 Non-ionic surface a c t i v e agents i n t e r a c t with preservative, decrease t h e i r antimicrobial a c t i v i t y , and a f f e c t the over-all absorption of t h e medicaments35. Polysorbate 20 and a polyelec r o l y t e d i s p e r s a n t increased t h e r e l e a s e r a t e s of s o l i d s i n microcapsules3 Chemical, physical and morphological reasons for t h e permeation of various chemical s t r u c t u r e s through p l a s t i c m a t e r i a l s were postulated37. A s e r i e s of s t r u c t u r a l l y r e l a t e d aromatic compounds were studied f o r t h e i r a b i l i t y t o permeate through a polyethylene f i l m . Benzyl alcohol and benzo c acid had the lowest permeability due t o intermolecular hydrogen bonding3
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The t h e o r e t i c a l bases for formulation of s t a b l e drugs Drug S t a b i l i t y depend upon knowledge of t h e k i n e t i c s of t h e thermal s o l v o l y s i s of t h e drug i n solution a s a function of pH, concentration and excipients. This sectt i o n considers recent fundamental contributions on t h e k i n e t i c s and mechrs on t h e k i n e t i c s and anisms of drug s t a b i l i t y . A series of review A complete and c r i t i s t a b i l i t y of drugs ha r e c e n t l y been published c a l review by GarrettE2 of t h e a v a i l a b l e l i t e r a t u r e up t o 1966 on k i n e t i c s and mechanisms i n t h e s t a b i l i t y of drugs is now available. The hydrolysis of undissociated a s i r i n i n buffered s o l u t i o n s of t h e non-ionic surfacta n t s , cetomacrogel$? and polysorbate 80N i s i n h i b i t e d due t o t h e p a r t i t i o n of, and t h u s t h e u n a v a i l a b i l i t y i n t r u e s o l u t i o n of, aspirin4?, A s p e c i f i c hydrogen ion catalyzed hydrolysis of t h e undissociated a s p i r i n p a r t i t i o n e d i n t o t h e micelles i s observed but i s of a smaller magnitude than i t s count e r p a r t i n t r u e solution. Dissociated a s p i r i n i s not p a r t i t i o n e d and shows o v e r a l l i n h i b i t i o n of s o l v o l y t i c r a t e i n t h e presence of t h e s u r f a c t a n t Cyclodextrin enhances t h e hydrolysis of a s p i r i n a t elevated H values The but i n h i b i t s t h e hydrolyses of e t h y l aminobenzoates and atropine 4F former i s ascribed t o t h e s t e r i c juxtaposition of ionized hydroxyl groups t o bound a s p i r i n whereas t h e l a t t e r i s ascribed t o inclusion henomena where t h e solution a v a i l a b i l i t y of t h e s u b s t r a t e s i s reduced'y. It was a l s o shown t h a t t h e s p e c i f i c hydroxyl ion catalyzed hydrolysis of benzocaine and homatropine i n t h e presence of nonionic surface-act e agents i s unaffected a t l e s s than t h e c r i t i c a l micelle concentration However, a t a concentration i n excess, t h e s t a b i l i t y i s enhanced due t o m i c e l l a r i n t e r a c t i o n or p a r t i t i o n . Fersht and Kirby47 have demonstrated t h a t t h e pH independent region f o r t h e s o l v o l y s i s of a s p i r i n i s due t o t h e f a c t t h a t t h e ionized carboxyl group a c t s a s a general base i n i t s a t t a c k on water t o form t h e hydroxyl ion t h a t a t t a c k s t h e ester, r a t h e r than t h e previously accepted mechanism of intramolecular nucleophilic a t t a c k on e ste r carboxyl carbon t h a t r e s u l t s i n a mixed anhydride. This occ).~gs when a s p i r i n i s s u b s t i t u t e d with highly e l e c t r o n withdrawing groups General base c a t a l y s i s by a c e t a t e and phosphate was a l s o demonstrated. The a t t a c k of nucleophiles on t h e ester group i s promoted by intramolecular e n e r a l acid c a t a l y s i s effected by t h e undissociated carboxylic acid group45 ,
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Schwartz5', a s p a r t of a continuing and d e t a i l e d series on model cata l y s t s which simulate p e n i c i l l i n a s e has studied t h e mechanism of hydrolysis of p e n i c i l l i n catalyzed by catachol and t h e i r pH dependencies. The degra-
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dation of 6-aminopenici~1anic a c i d by s o l v o l y s i s of t h e B-lactam i s first order below pH 6.6 and tends toward second order with r e s p e c t t o s u b s t r a t e above t h i s valuefii. The pH of minimum s o l v o l y s i s i s 8.0. A concomitant reaction is dimerization through t h e nucleophilic a t t a c k of t h e amino group of one molecule t o t h e B-lactam of another t o form p e n i c i l l i n . The k i n e t i c s of a series of 3,b-dialkylsydnones were studied where t h e presence of ana-hydrogen i o n on t h e a l k y l s u b s t i t u e n t s tended t o s t a b i l i z e a g a i n s t hydrogen ion and water a t t a c k , probably by decreasing t h e concent r a t i o n of a r e a c t i v e intermediate with e q u i l i b r a t e d tautomeric f0ms5~. The rate-pH p r o f i l e nd Arrhenius' parameters have been determined f o r echothiophate iodide33 The k i n e t i c s show a pH independent s o l v o l y s i s with
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t h e l o s s of one mole of ethanol and a s p e c i f i c hydroxyl ion a t t a c k on t h e S-P bond t o f i e l d ( 2-mercaptoethyl)-trimethylamonium iodide. Notari54 has s t a t e d t h a t t h e primary mechanism of hydrolytic deamination of cytosine arabinoside appears t o r e s u l t f r m t h e a t t a c k of t h e nucleophilic monoanion of a polybasic a c i d ( b i s u l f i t e , dihydrophosphate, etc.) with a r e a d i l y d i s s o c i a b l e proton on t h e activated C-6 p o s i t i o n of t h e protonated nucleoside, I, with subsequent s a t u r a t i o n a t t h e C-5 p o s i t i o n by t h e l a b i l e proton, 11. Subsequent nucleophilic displacement by H,O occurs a t C-4 with a l o s s of NH,. The products I1 and I11 a r e i s o l a b l e . Further alkal i n e treatment can regenerate t h e u r a c i l arabinoside
The hydrolytic r a t e s of various N-substituted 6-amino-thiouracils t o t h e corresponding 6-aminouracils were compared i n strongly a c i d i c and alkal i n e s o l u t i o n s and were enhanced over t h e unsubstituted compound55. A t high acid concentrations, t h e pH independent a t t a c k of water on t h e protonated species becomes rate-determining. The r a t e s of formation of hydroxymethylfurfural from f r u c t o s e and sucrose56, of f u r f u r a l from ribosefi7, and of t h e now i d e n t i f i e d 5-methyl-3( 2H)-furanone from 2-deoxy-D-ribo~e5~ have been characterized a s a function of temperature and acid concentration. The k i n e t i c s of degradation of these products hav en characterized a s a function of temperature and a l k a l i concentration5 Isoniazid shows an anerobic hydrogen ion catalyzed s o l v o l y s i s with s i g n i f i c a n t b u f f e r e f f e c t s t o i s o n i c o t i n i c acid t h a t can be assigned to'hydrogen ion a t t a c k on t h e monocation or water a t t a c k on t h e dication59. Certain s u l f a drugs such a s 2-sulfanylamido-~,5-dimethyloxazole and 3- sulfanylamido-2-phenyl-pyrazole a r e highly sugSeptible t o oxidative degradation through sulfanylurea t o sulfanylamide The i n t e r e s t i n g observation of an unusual acid-catalyzed s o l v o l y s i s of an anhydride was obse ved by Nestler and Seydel i n the case of t h e i s o n i c o t i n i c acid anhydridesgl. The k i n e t i c s of s o l v o l y s i s of 2ethylpyridine-4-carboxythioamide have been described. It undergoes solvent and s p e c i f i c acid catalyzed s o l v o l y s i s t o t h e corresponding carboxylamide and carboxyl, and i n a l k a l i forms both s t a b l e carboxylic acid
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The r e a c t i o n of t h e food preservative, deand thiocarboxylic acid&. hydroacetic acid with amino compounds under i n v i t r o physiological condit i o n s has been studied i n e t h a n o l i c solutions. Schiff base formation a s a function of pH is maximal 3.pH 7 and i s c o n s i s t e n t with t h e c l a s s i c a l mechan sn of a t t a c k of undissociated amines on t h e protonated carbonyl The u s e of carbonate esters a s "prodrugs"which possess d e s i r a b l e carbon h3 pharmaceutical p r o p e r t i e s and can r e l e a s e pharm c o l o g i c a l l y a c t i v e compounds on hydrolysis i n vivo has been suggestedg4 and thus he study of t h e i r enzymatic hydrolysis of a-chymotrypsin was conducted 65 The r a t e s were proportional t o enzyme and s u b s t r a t e concentration where t h e former could b e saturated i n accordance with t y p i c a l Michaelis-Menten kinetics. A sigmoid pH-rate curve is obtained c h a r a c t e r i s t i c of an enzyme function of pKa2. There is a very r a p i d production of alcohol, Pi, and a subsequent s l o er r a t e when enzyme concentration, E, i s d e f i c i e n t . This can be explained 5 on t h e premise t h a t t h e regeneration of enzyme, E, along with t h e acyl moiety, P, from a p a r t i a l l y dissociated enzyme complex ES' becomes r a t e determining E + S m E S d P , + ES1-+P2 + E An apparatus f o r s o l u t i o n k i n e t i c s t o minimize l a g t m e f o r thermal equilThe maintenance i b r a t i o n and oxygen contamination has been describedk6 of constant spectrophotometric absorbance of an acid-base i n d i c a t o r while monitoring added acid-base r e a c t a n t has been pro osed and evaluated t o maintain constant pH i n t h e hydrolysis of esters 7.
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--Pharmacokinetics and Biophannaceutics - The q u a n t i f i c a t i o n of t h e d i s t r i b u t i o n s of a c u t e doses of a drug and i t s metabolites i n t h e multicompartment-
a 1 complex organismand i t s r a t e s of metabolism and excretion a s functions of dose a r e necessary p r e r e q u i s i t e s f o r t h e determination of i t s b i o l o g i c a l a v a i l a b i l i t y f r o m dosage forms and depends on perturbations of t h e timecourse of observed d i s t r i b u t i v e patterns. The l i m i t a t i o n s of t h e simplifying hypothesis of a r a p i d l y e q u i l i b r a t i n g t o t a l volume of d i s t r i b u t i o n t o v a l i d l y estimate t h e first order r a t e constants f o r loss of drug f r o m t h e blood and for accumulation i n t h e u r i n e have r e c e n t l y been appreciated f3,69. Examples of t h e i n v a l i d i t y of t h i s hypothesis a r e referenced i n a discussion of t h e l i m i t i n g conditions for observing simple exponential loss of drug from t h e blood plasma7O. This simplifying p o s t u l a t e i s s t i l l used irst order appearance and i n computer programs f o r the simple model first order removal of drug frcm the bloodqf*'2 which permit determination of both r a t e constants even when they a r e of s i m i l a r magnitude72. Methods have been proposed73 f o r estimating f i r s t order r a t e constants of absorption, metabolite formation and o v e r a l l l o s s of drug from t h e body when t h e t i m e course f o r urinary excretion of a metabolite i s known and t h e r a t e constant f o r urinary excretion of t h e metabolite is available. Wagner74 has claimed t h a t evaluation of t h e time course of urinary excretion of metabolites on t h e assumption of rapid clearance may lead t o an erroneous conclusion of s a t u r a t i o n of metabolic pathways. H e a l s o s t a t e d t h a t t h e apparent l i n e a r i t y of a cumulative urinary excretion curve and/or t h e curvature of semilogarithmic p l o t s of drug blood l e v e l s or of amounts of drug-not-excreted a g a i n s t t i m e a r e i n s u f f i c i e n t evidences t o conclude zero order s t e p s i n metabolite production o r zero order absorption
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of a drug. He used data i n t h e l i t e r a t u r e on a s p i r i n phannacokinetics a s h i s examples. Levy75has claimed t h a t a d d i t i o n a l and strong evidence i s a v a i l a b l e f o r t h e pharmacokinetic model f o r s a l i c y l a t e elimination i n man which assumes capacity-limited o r zero order formation of s a l i c y l u r i c acid a t higher doses. If t h e time-course of drug l e v e l s i n t h e accessible compartments of t h e body i s c o r r e l a t e d with t h e time-course of pharmacological a c t i v i t y , i n s i g h t can be gained i n t o t h e p r o p e r t i e s of t h e compartment i n which reside t h e receptor s i t e ~ 7 ~ 9 ~Methatrimeprazine 6. levels i n t h e b r a i n were correlated with t h e onset and duration of pharmacologic e f f e c t s and implicated d i r e c t a c t i o n and d i s t r i b u t i o n of t h e parent compound The overt u r n time f o r goldfish and i t s duration were used a s a phannacologic endpoint f o r t h e a c t i o n of ethanol and pentobarbi a 1 and i s a function of body drug l e v e l s and r a t e of drug elimination 78
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Urinary excretion studies79 have shown t h a t riboflavin-5 * -phosphate and r i b o f l a v i n a r e incompletely absorbed i n t h e upper region of t h e gastroi n t e s t i n a l t r a c t and t h e absorption sites appear t o be s a t u r a b l e since t h e percent recovery decreases with increasing o r a l dose. Enterohepatic cyc l i n g i s a l s o indicated. Probenecid i n h i b i t s t h e specialized t r a n s p o r t process responsible f o r the i n t e s t i n a l absorption of r i b o f l a v i n i n man and apparently i n h i b i t s t h e a c t i v e r e n a l tubular secretory process, thereby increasing t h e apparent blood l e v e l half-life80. Further work has been c a r r i e d out on t h e pharmacokinetic model f o r n a l i d i x i c acid i n man81. The blood l e v e l s on repeated dosing could be predicted from t h e pharmacokinetic model obtained from t h e study of an a c u t e dosage and demonstrated no satu r a t i o n o r induction e f f e c t s . The pharmacokinetics and metabolism of 5methylpyrazole-3-carboxylic acid has been studied i n the r a t , dog and human and no v a r i a t i o n s i n t h e pharmacokinetic parameters were observed on chronic dosing. The drug i s completely absorbed and r a p i d l y excreted with an a c i d i c conjugate a s a p a r t i a l metabolite i n t h e r a t and man82. The apparent h a l f - l i f e of diazoxide i n t h e blood of man was determined t o be 28* 8.3 hrs.83. Thiothixene i s w e l l absorbed, r a p i d l y d i s t r i b u t e d and rn tabolized t o products which a r e b i l i a r y e ~ c r e t e d 8 ~ .The absorption of l'b-labelled teroxalene H C 1 i n various species showed a l i n e a r r e l a t i o n t o o r a l dose and apparent f i r s t order elimination although l a r g e r e s i d u a l s were maintained i n adipose tissue85. The absorption, excretion and metabolism of dimethylsulfoxide has been studied i n man and un hanged drug and t h e metabolite dimethylsulfone a r e excreted i n t h e urinebg. Salicylamide i s eliminated a s t h e glucuronide and the s u l f a t e , t h e former decreasing w i t h increasing dose and t h e l a t t e r increasing and imply s a t u r a t i o n proc e ~ s e s ~Probenecid ~ . i n h i b i t s e f f l u x of 5-hydroxyindoleacetic acid from r a t b r a i n t o plasma i n steady-state k i n e t i c studies88. Rifampicin, a new rifamycin, has been pharmacokinetically studied a s t o absorption, d i f f u sion and elimination i n human&. The pharmacokinetics and metabolism of chlormezanone has been studied i n man and laboratory animals9O. p-Methoxycinnamate i s r a p i d l y absorbed i n r a b b i t s and is r a p i d l y metabolized t o p-metho~ybenzoate9~. Blood l e v e l h a l f - l i v e s are g r e a t e r on o r a l than on intraveneous administration. The maximum concentration i n t h e blood i s proportional t o t h e dose. The f i r s t order l o s s of intravenously adminis t e r e d bishydroxycoumarin, l e v e l s i n plasma has been compared f o r t h e r a t ,
Chap. 3 2
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Garrett, Araujo
343 -
guinea pig, dog and rhesus monkey92. Only i n t h e monkey was it d e f i n i t i v e t h a t t h e h a l f - l i f e increased with increasing dose. Methyridine is r a p i d l y absorbed and d i s t r i b u t e d i n sheep, calves and cows on various r o u t e s of administration93. The major metabolite i s pyrid-2-ylacetic a c i d which i s a l s o excreted a s a glycine conjugate. Increase of drug dosage t o compens a t e for enzyme induction may r e s u l t i n marked toxicitiesg4. D i f f e r e n t their toxicities administrative routes of cholinesterase i n h i b i t o r s vary and it is suggested t h a t t h e a v a i l a b i l i t y f o r metabolism i n t h e l i v e r i s t h e major factor95. The t o t a l urinary excretion of amphetamine i s pH dependent b u t t h e r e i a d e f i n i t i v e d i f f e r e n c e i n t h e r e l a t i v e excretion The pharmacokinetic models f o r cyproterone acer a t e s of t h e isomers9 t a t e were s i m i l a r i n men and baboons and s i g n i f i c a n t g a s t r o i n t e s t i n a l resorption was 0bserved9~.
8.
On t h e hypothesis t h a t modifications of t h e r a t e of drug absorption may c o n t r o l or reduce nausea and/or emesis associated with t h e d i f f i c u l t l y soluble n i t r o f u r a n t o i n administration, t h e c r y s t a l s i z e was controlled and a v a i l a b i l i t y i n r a t , dog and man, and emesis i n t h e dog were shown t o increase a s a function of t h e a v a i l a b l e surface area of f i n e c r y s t a l s98 Griseofulvin absorption i n man c o r r e l a t e d with i t s d i s s o l u t i o n r a t e s i n various f ormulations i n simulated i n t e s t i n a l fluids99. The time-courses of dextroamphetamine 1 k s u l f a t e 1 0 0 i n dogs and humans and amobarbital14C i n humans101 were monitored i n plasma and urine t o compare t h e availab i l i t y from sustained and nonsustained-release dosage forms. Biological a v a i l a b i l i t y from various formulations f o r r e c t a l absorptionloz, 103 were determined from blood levels. Pla a l e v e l s of phenmetrazine were evaluated from d i f f e r e n t formulationslO? Relative absorption r a t e s of pente e r y t h r i t o l t e t r a n i t r a t e from l i g a t e d s e c t i o n s of t h e g a s t r o i n t e s t i n a l t r a c t were a t t r i b u t e d t o i t s degradation i n t o lower n i t r a t e s l 0 5 . Absorpt i o n of quinine hydrochloride from e n t e r i c coated t a b l e t s has been monit o r e d by plasma and urinary l e v e l s with time a d i t s absorption i s decreased i n t h e d i s t a l p a r t s of t h e intestinelo'. Urinary excretion data was used t o s t u d y t h e r e l e a s e r a t e i n vivo of a n t i p y r e t i c and analgesic drugs from commercial sugar-coated t a b l e t s l o 7 . Polysorbate 80 enhances t h e absorption of s e c o b a r b i t a l i t h e goldfish by increasing t h e p e m e a b i l i t y of t h e b i o l o g i c a l mernbranelo8. The e f f i c i e n c y of t e t r a c y c l i n e absorption i n d i f f e r e n t s u b j e c t panels has been shown t o be s i m i l a r based on t h e seq u e n t i a l first order model of absorption and excretion and premise t h a t t h e area under t h e blood level-time curve i s r e l a t e d to t h e r e l a t i v e absorption efficiencylO9. Similar procedures have been used t o compare t h e e n t e r a l absorption of sulfanilamidesllo. Levy111 has demonstrated s i g n i f i c a n t d i f f e r e n c e s i n t h e phannacokinetic constants f o r benzyl p e n i c i l l i n i n humans when ambulatory o r during bed rest which may be a t t r i b t u t e d t o v a r i a t i o n s i n apparent volumes of d i s t r i b u t i o n t h a t a f f e c t apparent metab o l i c r a t e s . S i g n i f i c a n t d i f f e r e n c e s i n d i s s o l u t i o n r a t e s may a f f e c t s a l i c y l a t e a v a i l a b i l i t y i n individuals with high absorption r a t e s b u t not those t h a t a r e slow absorbers21.
.
Amphetamines blocked i n t h e para p o s i t i o n r d t h a chlorine disappeared f r o m t h e b r a i n a t slower r a t e s which could be a t t s i b u t e d to t h e blocking of t h e para hydroxylation route112. Four u r i n a r y metabolites of N-(0-aminophenyl) N- dimethylaminopropyl ) a n t h r a n i l a t e h ve been i d e n t i f ied i n t h e
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dog and humanll3. The k i n e t i c s of excretion of the drug and i t s metabolites have indicated t h a t absorption and metabolism take place r a p i d l y and t h a t t h e b i l i a r y r o u t e i s t h e major one i n excretion. Equilibrium d i a l y s i s s t u d i e s of t h e p r o t e i n binding of c o r t i s o l show t h a t t h e chemical degradat i o n i n the f i n i t e time of t h e study give erroneous estimates of t h e binding i f not accounted forii4. Biopharmaceutical considerations i n subcutaneous and intramuscular drug administration have been reviewed recent1 ~ 1 1 5a s has t h e mechanisms of drug absorption and excretionll6. There has been a r e c e n t awareness t h a t metabolic and d i s t r i b u t i v e p a t t e r n s vary among i n d i v i d u a l s f o r t h e same drugsll7r70 and t h a t i n t h e f u t u r e t h e metabolic and pharmacokinetic p r o f i l e s of i n d i v i d u a l s w i l l be mapped before prescribing drugs and dosage regimens. References
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Topics in Chemistry
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Garrett, Araujo
Chapter 32.
Phannaceutics, Pharmacokinetics and Biophannaceutics Edward R. G a r r e t t and Oscar E. Araujo College of Pharmacy, University of Florida, Gainesville, FL 32601
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Introduction The a v a i l a b i l i t y of t h e drug from t h e dosage form depends on physical chemical f a c t o r s , chemical i n t e r a c t i o n s and a p r i o r i p r e d i c t i o n s and confirmations of r e l e a s e i n b i o l o g i c a l systems.
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Drug Dissolution and Diffusion The importance of t h e r e l a t i o n s h i p between drug absorption and t h e r a t e processes of d i f f u s i o n and d i s s o l u t i o n has been w e l l established i n recent years. W. Higuchil has reviewed t h e lite r a t u r e and extracted t h e physical and mathematical treatments of drug transport. He considered t h e laws governing t h e d i s s o l u t i o n r a t e s of solids a s affected by a g i t a t i o n , p a r t i c l e s i z e , i n t e r a c t i o n with s o l u t i o n a d d i t i v e s and drug r e l e a s e r a t e s from matrices t h a t do and do not obey Fick's law. The d i f f u s i o n r a t e s of pentobarbital, s a l i c y l i c acid and urea across t h e i s o l a t e d r a b b i t mesentery i n d i c a t e d i f f u s i o n of both i o n i c and non-ionic forms of t h e drugs across t h e membrane. with no s i g n i f i c a n t change i n r a t e due t o pH2. Drug t r a n s p o r t through nonpolar l i q u i d s a s models of l i v i n g membranes indicated t h a t when t h e Hildebrand 6 value of t h e drug molecule apprcached t h a t of t h e l i p o i d a l b a r r i e r , t r a n s er of t h e drug molecule across and through t h e l i p o i d a l b a r r i e r was faster When aqueous d i f f u s i o n a l b a r r i e r s on each s i d e of t h e l i p o i d a l membrane a r e included, Fick's law does n o t f u l l y hold i n t h i s case of protonation of weak bases4. The t r a n s f e r of amidopyrine and s a l i c y l i c acid through an organic l i q u i d obeys t h e t h e o r e t i c a l equation proposed5. The formation of complexes can modify t h e r a t e of t r a n s f e r of drugs t rough such b a r r i e r s and demand modification of t h e d i f f u s i o n a l equations When micron-sized emulsion d r o p l e t s a c t as sinks f o r drug, equations were derived for m i c e l l a r s o l u b i l i z a t i o n t o t a k e i n t o account t h e possible e f f e c t s of an e l e c t r i c a l b a r r i e r between t h e micelle and t h e charged oil-water i n t e r f a c e .? Drug r e l e a s e from water i n o i l emulsions a s a function of pH i n t o an aqueous sink8 and with a separating membrane9 was studied and t h e experimental data agreed with the physical models suggested. I n order f o r i n v i t r o d i s s o l u t i o n s t u d i e s of poorly soluble drugs t o bear any r e l a t i o n s h i p t o & vivo observations, s i n k conditions must be maintained and t h i s can be s i m ulated by t h e presence of an organic solvent phaselo. The k i n e t i c s of simultaneous determinations of v i t r o drug d i s s o l u t i o n and p a r t i t i o n i n g r a t e s i n a s i n g l e system has been studied, a s affected by a g i t a t i o n and temperatwell. The e f f e c t of d i f f e r e n t polymorphic forms on t h e rate of d i s s o l u t i o n and subsequent absorption of a drug has been s h m t o be of extreme importance before recent governmental committees. Suspensions cont a i n i n g only chloramphenicol polymorph B gave s i g n i f i c a n t l y higher blood l e v e l s than suspensions containing only polymorph A, r e g a r d l e s s of p a r t i c l e
5.
2.
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3 38 -
Sect. VI
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sizel2. The r a t e s of reversion of t h e metastable t o t h e s t a b l e f o n s duri n g d i s s o l u t i o n were c o r r e l a t e d t o t h e c r y s t a l growth r a t e s f o r polymorphs of s u l f a t h i a z o l e and methylprednisolone13. Solvents have a d i s t i n c t influence on t h e shape of c E s t a l s and can promote t h e formation of unstable polymorphic modifications
.
P a r t i c l e s i z e has a decided e f f e c t on t h e r a t e of d i s s o l u t i o n of drugs. Examples of t h e i n t e r r e l a t i o n of p a r t i c l e s i z e , s o l u b i l i t y , absorption and t h e r a p e u t i c a c t i v i t y i l l u s t r a t e t h e i r importance i n medicin a l s f o r o r a l , t o p i c a l or p a r e n t e r a l administrationl5. The angle of repose and s l i d i n g angles of sodium borate and b o r i c a c i d powders were calcul a t e d and it was found t h a t t h e cohesive f o r c e between t h e p a r t i c l e s i s n e g l i g i b l y small f o r p a r t i c l e diameters l a r g e r than t h e c r i t i c a l while it s i g n i f i c a n t l y influences t h e angle a t smaller diameterslg:ZeThe apparent s p e c i f i c volume of samples i n t h e l o o s e s t packing i s n e a r l y cons t a n t f o r sizes above t h e c r i t i c a l diameter, b u t it i n c r e a s e s gradually The an l e s with decreasing p a r t i c l e s i z e below t h e c r i t i c a l diameter1?. of repose were a p a r e n t l y lowered by t h e a d d i t i o n of t h e lubricantsl!. The Coulter counter 15 was used t o study t h e p a r t i c l e s i z e d i s t r i b u t i o n of vari o u s samples of griseofulvin. The considerable d i f f e r e n c e s which would a f f e c t s p e c i f i c s u r f a c e area and thus blood l e v e l s demanded s t r i c t e r o f f i c i a l specifications20. Dissolution test procedures which have not been c a l i b r a t e d on t h e b a s i s of i n vivo measurements a r e u n l i k e l y t o r e f l e c t t h e g a s t r o - i n t e s t i n a l absorption and may i n f a c t y i e l d misleading dataz1. I n t r i n s i c dissolution r a t e s varied con i d e r a b l y among t a b l e t s f o r aspirin22, sodium s a l i c y l a t e 2 3 and phenindione2', depending on t h e c r y s t a l l i n e form, compression and tabl e t technology. A new d i s s o l u t i o n apparatus permits 20 d i s s o l u t i o n t e s t s simultaneously and t h e r e s u l t s agree w e l l with standard procedures*S.
-
Drug I n t e r a c t i o n s The f i r s t order r a t e s of deaggregation abbetted by wett i n g and d i s p e r s i n g agents of a suspension o f a s u b s t i t u t e benzoic acid and i t s sodium s a l t c o r r e l a t e with t h e r a t e s of solution2 The t h e o r e t i c a l simultaneous r e l e a s e o f a mixture of two non-interacting drugs d i s persed i n an i n e r t p l a s t i c matrix was confirmed by s t u d i e s on a s a l i c y l i c acid-benzoic a c i d p l a s t i c mixture27. The v a l i d i t y of t h e model f o r t h e int e r a c t i n g system, benzocaine-caffeine, was also verified28. Surprisingly, t h e r e l e a s e of s a l i c y l i c a c i d from polyethylene matrices exhibited no r a t e i n c r e a s e i n t h e presence of increasing concentrations of d i b a s i c potassium phosphate even though t h e s o l u b i l i t y increased a s much a s 45 fold. The presence of a s u r f a c t a n t , however, produced a dramatic r a t e increase. The r e s u l t indicated t h a t matrix permeability and r a t e s of permeation by t h e solvent can r e s t r i c t drug r e l e a s e r a t e s a s a function of pore s i z e d i s t r i bution of t h e matrix and wetting p r o p e r t i e s of t h e solvent defined by surf a c e tension and contact angle29. The r e l e a s e of benzoic a c i d and salicyl i c acid i n t o aqueous media from wax matrices a r e b e s t analyzed from a d i f f u s i o n c o n t r o l l e d model and square r o o t of t i m e r e l e a s e profiles30. Over one range of composition t h e r a t e of r e l e a s e of a hydrogenated c a s t o r o i l propylene glycol monostearate-sulfanilamide i s d i f f u s i o n controlled, with high t o f t n o s i t y values. A t higher sulfanilamide concentrations i n t h e tabl e t . t h e r e l e a s e i s not d i f f u s i o n controlled31. Dissolution r a t e s of
2.
Chap. 32
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hexestrol, d i e n e s t r o l and griseofulvin increased s i g n i f i c a n t l y i n t h e presence of l y ~ o l e c i t h i n 3a ~s they did f o r t e s t o s t e r o n e i n aqueous s o l u t i o n s of polysorbates33. I n general, increasing conc n t r a t i o n s of surface-active agents increase t h e d i s s o l u t i o n r a t e s of drugs3 Non-ionic surface a c t i v e agents i n t e r a c t with preservative, decrease t h e i r antimicrobial a c t i v i t y , and a f f e c t the over-all absorption of t h e medicaments35. Polysorbate 20 and a polyelec r o l y t e d i s p e r s a n t increased t h e r e l e a s e r a t e s of s o l i d s i n microcapsules3 Chemical, physical and morphological reasons for t h e permeation of various chemical s t r u c t u r e s through p l a s t i c m a t e r i a l s were postulated37. A s e r i e s of s t r u c t u r a l l y r e l a t e d aromatic compounds were studied f o r t h e i r a b i l i t y t o permeate through a polyethylene f i l m . Benzyl alcohol and benzo c acid had the lowest permeability due t o intermolecular hydrogen bonding3
8.
2. -
&.
The t h e o r e t i c a l bases for formulation of s t a b l e drugs Drug S t a b i l i t y depend upon knowledge of t h e k i n e t i c s of t h e thermal s o l v o l y s i s of t h e drug i n solution a s a function of pH, concentration and excipients. This sectt i o n considers recent fundamental contributions on t h e k i n e t i c s and mechrs on t h e k i n e t i c s and anisms of drug s t a b i l i t y . A series of review A complete and c r i t i s t a b i l i t y of drugs ha r e c e n t l y been published c a l review by GarrettE2 of t h e a v a i l a b l e l i t e r a t u r e up t o 1966 on k i n e t i c s and mechanisms i n t h e s t a b i l i t y of drugs is now available. The hydrolysis of undissociated a s i r i n i n buffered s o l u t i o n s of t h e non-ionic surfacta n t s , cetomacrogel$? and polysorbate 80N i s i n h i b i t e d due t o t h e p a r t i t i o n of, and t h u s t h e u n a v a i l a b i l i t y i n t r u e s o l u t i o n of, aspirin4?, A s p e c i f i c hydrogen ion catalyzed hydrolysis of t h e undissociated a s p i r i n p a r t i t i o n e d i n t o t h e micelles i s observed but i s of a smaller magnitude than i t s count e r p a r t i n t r u e solution. Dissociated a s p i r i n i s not p a r t i t i o n e d and shows o v e r a l l i n h i b i t i o n of s o l v o l y t i c r a t e i n t h e presence of t h e s u r f a c t a n t Cyclodextrin enhances t h e hydrolysis of a s p i r i n a t elevated H values The but i n h i b i t s t h e hydrolyses of e t h y l aminobenzoates and atropine 4F former i s ascribed t o t h e s t e r i c juxtaposition of ionized hydroxyl groups t o bound a s p i r i n whereas t h e l a t t e r i s ascribed t o inclusion henomena where t h e solution a v a i l a b i l i t y of t h e s u b s t r a t e s i s reduced'y. It was a l s o shown t h a t t h e s p e c i f i c hydroxyl ion catalyzed hydrolysis of benzocaine and homatropine i n t h e presence of nonionic surface-act e agents i s unaffected a t l e s s than t h e c r i t i c a l micelle concentration However, a t a concentration i n excess, t h e s t a b i l i t y i s enhanced due t o m i c e l l a r i n t e r a c t i o n or p a r t i t i o n . Fersht and Kirby47 have demonstrated t h a t t h e pH independent region f o r t h e s o l v o l y s i s of a s p i r i n i s due t o t h e f a c t t h a t t h e ionized carboxyl group a c t s a s a general base i n i t s a t t a c k on water t o form t h e hydroxyl ion t h a t a t t a c k s t h e ester, r a t h e r than t h e previously accepted mechanism of intramolecular nucleophilic a t t a c k on e ste r carboxyl carbon t h a t r e s u l t s i n a mixed anhydride. This occ).~gs when a s p i r i n i s s u b s t i t u t e d with highly e l e c t r o n withdrawing groups General base c a t a l y s i s by a c e t a t e and phosphate was a l s o demonstrated. The a t t a c k of nucleophiles on t h e ester group i s promoted by intramolecular e n e r a l acid c a t a l y s i s effected by t h e undissociated carboxylic acid group45 ,
fsm .
@g
.
.
ts.
.
Schwartz5', a s p a r t of a continuing and d e t a i l e d series on model cata l y s t s which simulate p e n i c i l l i n a s e has studied t h e mechanism of hydrolysis of p e n i c i l l i n catalyzed by catachol and t h e i r pH dependencies. The degra-
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dation of 6-aminopenici~1anic a c i d by s o l v o l y s i s of t h e B-lactam i s first order below pH 6.6 and tends toward second order with r e s p e c t t o s u b s t r a t e above t h i s valuefii. The pH of minimum s o l v o l y s i s i s 8.0. A concomitant reaction is dimerization through t h e nucleophilic a t t a c k of t h e amino group of one molecule t o t h e B-lactam of another t o form p e n i c i l l i n . The k i n e t i c s of a series of 3,b-dialkylsydnones were studied where t h e presence of ana-hydrogen i o n on t h e a l k y l s u b s t i t u e n t s tended t o s t a b i l i z e a g a i n s t hydrogen ion and water a t t a c k , probably by decreasing t h e concent r a t i o n of a r e a c t i v e intermediate with e q u i l i b r a t e d tautomeric f0ms5~. The rate-pH p r o f i l e nd Arrhenius' parameters have been determined f o r echothiophate iodide33 The k i n e t i c s show a pH independent s o l v o l y s i s with
.
(CH,),N+
- CH, - CH, - S - O(O)(O - C 2H 5) 2I-
t h e l o s s of one mole of ethanol and a s p e c i f i c hydroxyl ion a t t a c k on t h e S-P bond t o f i e l d ( 2-mercaptoethyl)-trimethylamonium iodide. Notari54 has s t a t e d t h a t t h e primary mechanism of hydrolytic deamination of cytosine arabinoside appears t o r e s u l t f r m t h e a t t a c k of t h e nucleophilic monoanion of a polybasic a c i d ( b i s u l f i t e , dihydrophosphate, etc.) with a r e a d i l y d i s s o c i a b l e proton on t h e activated C-6 p o s i t i o n of t h e protonated nucleoside, I, with subsequent s a t u r a t i o n a t t h e C-5 p o s i t i o n by t h e l a b i l e proton, 11. Subsequent nucleophilic displacement by H,O occurs a t C-4 with a l o s s of NH,. The products I1 and I11 a r e i s o l a b l e . Further alkal i n e treatment can regenerate t h e u r a c i l arabinoside
The hydrolytic r a t e s of various N-substituted 6-amino-thiouracils t o t h e corresponding 6-aminouracils were compared i n strongly a c i d i c and alkal i n e s o l u t i o n s and were enhanced over t h e unsubstituted compound55. A t high acid concentrations, t h e pH independent a t t a c k of water on t h e protonated species becomes rate-determining. The r a t e s of formation of hydroxymethylfurfural from f r u c t o s e and sucrose56, of f u r f u r a l from ribosefi7, and of t h e now i d e n t i f i e d 5-methyl-3( 2H)-furanone from 2-deoxy-D-ribo~e5~ have been characterized a s a function of temperature and acid concentration. The k i n e t i c s of degradation of these products hav en characterized a s a function of temperature and a l k a l i concentration5 Isoniazid shows an anerobic hydrogen ion catalyzed s o l v o l y s i s with s i g n i f i c a n t b u f f e r e f f e c t s t o i s o n i c o t i n i c acid t h a t can be assigned to'hydrogen ion a t t a c k on t h e monocation or water a t t a c k on t h e dication59. Certain s u l f a drugs such a s 2-sulfanylamido-~,5-dimethyloxazole and 3- sulfanylamido-2-phenyl-pyrazole a r e highly sugSeptible t o oxidative degradation through sulfanylurea t o sulfanylamide The i n t e r e s t i n g observation of an unusual acid-catalyzed s o l v o l y s i s of an anhydride was obse ved by Nestler and Seydel i n the case of t h e i s o n i c o t i n i c acid anhydridesgl. The k i n e t i c s of s o l v o l y s i s of 2ethylpyridine-4-carboxythioamide have been described. It undergoes solvent and s p e c i f i c acid catalyzed s o l v o l y s i s t o t h e corresponding carboxylamide and carboxyl, and i n a l k a l i forms both s t a b l e carboxylic acid
%-B.
.
Chap. 3 2
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The r e a c t i o n of t h e food preservative, deand thiocarboxylic acid&. hydroacetic acid with amino compounds under i n v i t r o physiological condit i o n s has been studied i n e t h a n o l i c solutions. Schiff base formation a s a function of pH is maximal 3.pH 7 and i s c o n s i s t e n t with t h e c l a s s i c a l mechan sn of a t t a c k of undissociated amines on t h e protonated carbonyl The u s e of carbonate esters a s "prodrugs"which possess d e s i r a b l e carbon h3 pharmaceutical p r o p e r t i e s and can r e l e a s e pharm c o l o g i c a l l y a c t i v e compounds on hydrolysis i n vivo has been suggestedg4 and thus he study of t h e i r enzymatic hydrolysis of a-chymotrypsin was conducted 65 The r a t e s were proportional t o enzyme and s u b s t r a t e concentration where t h e former could b e saturated i n accordance with t y p i c a l Michaelis-Menten kinetics. A sigmoid pH-rate curve is obtained c h a r a c t e r i s t i c of an enzyme function of pKa2. There is a very r a p i d production of alcohol, Pi, and a subsequent s l o er r a t e when enzyme concentration, E, i s d e f i c i e n t . This can be explained 5 on t h e premise t h a t t h e regeneration of enzyme, E, along with t h e acyl moiety, P, from a p a r t i a l l y dissociated enzyme complex ES' becomes r a t e determining E + S m E S d P , + ES1-+P2 + E An apparatus f o r s o l u t i o n k i n e t i c s t o minimize l a g t m e f o r thermal equilThe maintenance i b r a t i o n and oxygen contamination has been describedk6 of constant spectrophotometric absorbance of an acid-base i n d i c a t o r while monitoring added acid-base r e a c t a n t has been pro osed and evaluated t o maintain constant pH i n t h e hydrolysis of esters 7.
.
.
2
.
%
--Pharmacokinetics and Biophannaceutics - The q u a n t i f i c a t i o n of t h e d i s t r i b u t i o n s of a c u t e doses of a drug and i t s metabolites i n t h e multicompartment-
a 1 complex organismand i t s r a t e s of metabolism and excretion a s functions of dose a r e necessary p r e r e q u i s i t e s f o r t h e determination of i t s b i o l o g i c a l a v a i l a b i l i t y f r o m dosage forms and depends on perturbations of t h e timecourse of observed d i s t r i b u t i v e patterns. The l i m i t a t i o n s of t h e simplifying hypothesis of a r a p i d l y e q u i l i b r a t i n g t o t a l volume of d i s t r i b u t i o n t o v a l i d l y estimate t h e first order r a t e constants f o r loss of drug f r o m t h e blood and for accumulation i n t h e u r i n e have r e c e n t l y been appreciated f3,69. Examples of t h e i n v a l i d i t y of t h i s hypothesis a r e referenced i n a discussion of t h e l i m i t i n g conditions for observing simple exponential loss of drug from t h e blood plasma7O. This simplifying p o s t u l a t e i s s t i l l used irst order appearance and i n computer programs f o r the simple model first order removal of drug frcm the bloodqf*'2 which permit determination of both r a t e constants even when they a r e of s i m i l a r magnitude72. Methods have been proposed73 f o r estimating f i r s t order r a t e constants of absorption, metabolite formation and o v e r a l l l o s s of drug from t h e body when t h e t i m e course f o r urinary excretion of a metabolite i s known and t h e r a t e constant f o r urinary excretion of t h e metabolite is available. Wagner74 has claimed t h a t evaluation of t h e time course of urinary excretion of metabolites on t h e assumption of rapid clearance may lead t o an erroneous conclusion of s a t u r a t i o n of metabolic pathways. H e a l s o s t a t e d t h a t t h e apparent l i n e a r i t y of a cumulative urinary excretion curve and/or t h e curvature of semilogarithmic p l o t s of drug blood l e v e l s or of amounts of drug-not-excreted a g a i n s t t i m e a r e i n s u f f i c i e n t evidences t o conclude zero order s t e p s i n metabolite production o r zero order absorption
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of a drug. He used data i n t h e l i t e r a t u r e on a s p i r i n phannacokinetics a s h i s examples. Levy75has claimed t h a t a d d i t i o n a l and strong evidence i s a v a i l a b l e f o r t h e pharmacokinetic model f o r s a l i c y l a t e elimination i n man which assumes capacity-limited o r zero order formation of s a l i c y l u r i c acid a t higher doses. If t h e time-course of drug l e v e l s i n t h e accessible compartments of t h e body i s c o r r e l a t e d with t h e time-course of pharmacological a c t i v i t y , i n s i g h t can be gained i n t o t h e p r o p e r t i e s of t h e compartment i n which reside t h e receptor s i t e ~ 7 ~ 9 ~Methatrimeprazine 6. levels i n t h e b r a i n were correlated with t h e onset and duration of pharmacologic e f f e c t s and implicated d i r e c t a c t i o n and d i s t r i b u t i o n of t h e parent compound The overt u r n time f o r goldfish and i t s duration were used a s a phannacologic endpoint f o r t h e a c t i o n of ethanol and pentobarbi a 1 and i s a function of body drug l e v e l s and r a t e of drug elimination 78
.
.
Urinary excretion studies79 have shown t h a t riboflavin-5 * -phosphate and r i b o f l a v i n a r e incompletely absorbed i n t h e upper region of t h e gastroi n t e s t i n a l t r a c t and t h e absorption sites appear t o be s a t u r a b l e since t h e percent recovery decreases with increasing o r a l dose. Enterohepatic cyc l i n g i s a l s o indicated. Probenecid i n h i b i t s t h e specialized t r a n s p o r t process responsible f o r the i n t e s t i n a l absorption of r i b o f l a v i n i n man and apparently i n h i b i t s t h e a c t i v e r e n a l tubular secretory process, thereby increasing t h e apparent blood l e v e l half-life80. Further work has been c a r r i e d out on t h e pharmacokinetic model f o r n a l i d i x i c acid i n man81. The blood l e v e l s on repeated dosing could be predicted from t h e pharmacokinetic model obtained from t h e study of an a c u t e dosage and demonstrated no satu r a t i o n o r induction e f f e c t s . The pharmacokinetics and metabolism of 5methylpyrazole-3-carboxylic acid has been studied i n the r a t , dog and human and no v a r i a t i o n s i n t h e pharmacokinetic parameters were observed on chronic dosing. The drug i s completely absorbed and r a p i d l y excreted with an a c i d i c conjugate a s a p a r t i a l metabolite i n t h e r a t and man82. The apparent h a l f - l i f e of diazoxide i n t h e blood of man was determined t o be 28* 8.3 hrs.83. Thiothixene i s w e l l absorbed, r a p i d l y d i s t r i b u t e d and rn tabolized t o products which a r e b i l i a r y e ~ c r e t e d 8 ~ .The absorption of l'b-labelled teroxalene H C 1 i n various species showed a l i n e a r r e l a t i o n t o o r a l dose and apparent f i r s t order elimination although l a r g e r e s i d u a l s were maintained i n adipose tissue85. The absorption, excretion and metabolism of dimethylsulfoxide has been studied i n man and un hanged drug and t h e metabolite dimethylsulfone a r e excreted i n t h e urinebg. Salicylamide i s eliminated a s t h e glucuronide and the s u l f a t e , t h e former decreasing w i t h increasing dose and t h e l a t t e r increasing and imply s a t u r a t i o n proc e ~ s e s ~Probenecid ~ . i n h i b i t s e f f l u x of 5-hydroxyindoleacetic acid from r a t b r a i n t o plasma i n steady-state k i n e t i c studies88. Rifampicin, a new rifamycin, has been pharmacokinetically studied a s t o absorption, d i f f u sion and elimination i n human&. The pharmacokinetics and metabolism of chlormezanone has been studied i n man and laboratory animals9O. p-Methoxycinnamate i s r a p i d l y absorbed i n r a b b i t s and is r a p i d l y metabolized t o p-metho~ybenzoate9~. Blood l e v e l h a l f - l i v e s are g r e a t e r on o r a l than on intraveneous administration. The maximum concentration i n t h e blood i s proportional t o t h e dose. The f i r s t order l o s s of intravenously adminis t e r e d bishydroxycoumarin, l e v e l s i n plasma has been compared f o r t h e r a t ,
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guinea pig, dog and rhesus monkey92. Only i n t h e monkey was it d e f i n i t i v e t h a t t h e h a l f - l i f e increased with increasing dose. Methyridine is r a p i d l y absorbed and d i s t r i b u t e d i n sheep, calves and cows on various r o u t e s of administration93. The major metabolite i s pyrid-2-ylacetic a c i d which i s a l s o excreted a s a glycine conjugate. Increase of drug dosage t o compens a t e for enzyme induction may r e s u l t i n marked toxicitiesg4. D i f f e r e n t their toxicities administrative routes of cholinesterase i n h i b i t o r s vary and it is suggested t h a t t h e a v a i l a b i l i t y f o r metabolism i n t h e l i v e r i s t h e major factor95. The t o t a l urinary excretion of amphetamine i s pH dependent b u t t h e r e i a d e f i n i t i v e d i f f e r e n c e i n t h e r e l a t i v e excretion The pharmacokinetic models f o r cyproterone acer a t e s of t h e isomers9 t a t e were s i m i l a r i n men and baboons and s i g n i f i c a n t g a s t r o i n t e s t i n a l resorption was 0bserved9~.
8.
On t h e hypothesis t h a t modifications of t h e r a t e of drug absorption may c o n t r o l or reduce nausea and/or emesis associated with t h e d i f f i c u l t l y soluble n i t r o f u r a n t o i n administration, t h e c r y s t a l s i z e was controlled and a v a i l a b i l i t y i n r a t , dog and man, and emesis i n t h e dog were shown t o increase a s a function of t h e a v a i l a b l e surface area of f i n e c r y s t a l s98 Griseofulvin absorption i n man c o r r e l a t e d with i t s d i s s o l u t i o n r a t e s i n various f ormulations i n simulated i n t e s t i n a l fluids99. The time-courses of dextroamphetamine 1 k s u l f a t e 1 0 0 i n dogs and humans and amobarbital14C i n humans101 were monitored i n plasma and urine t o compare t h e availab i l i t y from sustained and nonsustained-release dosage forms. Biological a v a i l a b i l i t y from various formulations f o r r e c t a l absorptionloz, 103 were determined from blood levels. Pla a l e v e l s of phenmetrazine were evaluated from d i f f e r e n t formulationslO? Relative absorption r a t e s of pente e r y t h r i t o l t e t r a n i t r a t e from l i g a t e d s e c t i o n s of t h e g a s t r o i n t e s t i n a l t r a c t were a t t r i b u t e d t o i t s degradation i n t o lower n i t r a t e s l 0 5 . Absorpt i o n of quinine hydrochloride from e n t e r i c coated t a b l e t s has been monit o r e d by plasma and urinary l e v e l s with time a d i t s absorption i s decreased i n t h e d i s t a l p a r t s of t h e intestinelo'. Urinary excretion data was used t o s t u d y t h e r e l e a s e r a t e i n vivo of a n t i p y r e t i c and analgesic drugs from commercial sugar-coated t a b l e t s l o 7 . Polysorbate 80 enhances t h e absorption of s e c o b a r b i t a l i t h e goldfish by increasing t h e p e m e a b i l i t y of t h e b i o l o g i c a l mernbranelo8. The e f f i c i e n c y of t e t r a c y c l i n e absorption i n d i f f e r e n t s u b j e c t panels has been shown t o be s i m i l a r based on t h e seq u e n t i a l first order model of absorption and excretion and premise t h a t t h e area under t h e blood level-time curve i s r e l a t e d to t h e r e l a t i v e absorption efficiencylO9. Similar procedures have been used t o compare t h e e n t e r a l absorption of sulfanilamidesllo. Levy111 has demonstrated s i g n i f i c a n t d i f f e r e n c e s i n t h e phannacokinetic constants f o r benzyl p e n i c i l l i n i n humans when ambulatory o r during bed rest which may be a t t r i b t u t e d t o v a r i a t i o n s i n apparent volumes of d i s t r i b u t i o n t h a t a f f e c t apparent metab o l i c r a t e s . S i g n i f i c a n t d i f f e r e n c e s i n d i s s o l u t i o n r a t e s may a f f e c t s a l i c y l a t e a v a i l a b i l i t y i n individuals with high absorption r a t e s b u t not those t h a t a r e slow absorbers21.
.
Amphetamines blocked i n t h e para p o s i t i o n r d t h a chlorine disappeared f r o m t h e b r a i n a t slower r a t e s which could be a t t s i b u t e d to t h e blocking of t h e para hydroxylation route112. Four u r i n a r y metabolites of N-(0-aminophenyl) N- dimethylaminopropyl ) a n t h r a n i l a t e h ve been i d e n t i f ied i n t h e
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dog and humanll3. The k i n e t i c s of excretion of the drug and i t s metabolites have indicated t h a t absorption and metabolism take place r a p i d l y and t h a t t h e b i l i a r y r o u t e i s t h e major one i n excretion. Equilibrium d i a l y s i s s t u d i e s of t h e p r o t e i n binding of c o r t i s o l show t h a t t h e chemical degradat i o n i n the f i n i t e time of t h e study give erroneous estimates of t h e binding i f not accounted forii4. Biopharmaceutical considerations i n subcutaneous and intramuscular drug administration have been reviewed recent1 ~ 1 1 5a s has t h e mechanisms of drug absorption and excretionll6. There has been a r e c e n t awareness t h a t metabolic and d i s t r i b u t i v e p a t t e r n s vary among i n d i v i d u a l s f o r t h e same drugsll7r70 and t h a t i n t h e f u t u r e t h e metabolic and pharmacokinetic p r o f i l e s of i n d i v i d u a l s w i l l be mapped before prescribing drugs and dosage regimens. References
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