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Chapter 9 Prodrugs and Drug Delivery Systems. Prodrug - a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation.

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Presentation on theme: "Chapter 9 Prodrugs and Drug Delivery Systems. Prodrug - a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation."— Presentation transcript:

1 Chapter 9 Prodrugs and Drug Delivery Systems

2 Prodrug - a pharmacologically inactive compound that is converted to an active drug by a metabolic biotransformation Ideally, conversion occurs as soon as the desired goal for designing the prodrug is achieved. Prodrugs and soft drugs are opposite: a prodrug is inactive - requires metabolism to give active form a soft drug is active - uses metabolism to promote excretion A pro-soft drug would require metabolism to convert it to a soft drug

3 1. Aqueous Solubility - to increase water solubility so it can be injected in a small volume 2. Absorption and Distribution - to increase lipid solubility to penetrate membranes for better absorption and ability to reach site of action 3. Site Specificity - to target a particular organ or tissue if a high concentration of certain enzymes is at a particular site or append something that directs the drug to a particular site

4 Utility of Prodrugs (cont’d) 4. Instability - to prevent rapid metabolism; avoid first-pass effect 5. Prolonged Release - to attain a slow, steady release of the drug 6. Toxicity - to make less toxic until it reaches the site of action 7. Poor Patient Acceptability - to remove an unpleasant taste or odor; gastric irritation 8. Formulation Problems - to convert a drug that is a gas or volatile liquid into a solid

5 I. Carrier-linked prodrug A compound that contains an active drug linked to a carrier group that is removed enzymatically A. bipartate - comprised of one carrier attached to drug B. tripartate - carrier connected to a linker that is connected to drug C. mutual - two, usually synergistic, drugs attached to each other II. Bioprecursor prodrug A compound metabolized by molecular modification into a new compound, which is a drug or is metabolized further to a drug - not just simple cleavage of a group from the prodrug

6 analogous to carrier-linked bioprecursor Keep in mind that a prodrug whose design is based on rat metabolism may not be effective in humans. analogous to SCHEME 9.1 Protecting group analogy for a prodrug

7 Most common activation reaction is hydrolysis.

8 1. Protect the drug until it reaches the site of action 2. Localize the drug at the site of action 3. Allow for release of drug 4. Minimize host toxicity 5. Are biodegradable, inert, and nonimmunogenic 6. Are easily prepared and inexpensive 7. Are stable in the dosage form

9 Most common prodrug form is an ester esterases are ubiquitous can prepare esters with any degree of hydrophilicity or lipophilicity ester stability can be controlled by appropriate electronic and steric manipulations

10 Ester analogs as prodrugs can affect lipophilicity or hydrophilicity

11 To accelerate the hydrolysis rate: attach an electron-withdrawing group if a base hydrolysis mechanism is important attach an electron-donating group if an acid hydrolysis mechanism is important To slow down the hydrolysis rate: make sterically-hindered esters make long-chain fatty acid esters


13 SCHEME 9.2 Intramolecular catalysis of succinate esters

14 Enolic hydroxyl groups can be esterified as well. antirheumatic agent


16 Can vary pK a by appropriate choice of R and R


18 Amides are commonly not used because of stability Activated amides (low basicity amines or amino acids) are effective pK a of amines can be lowered by 3 units by conversion to N-Mannich bases (X = CH 2 NHCOAr)

19 N-Mannich base (R = CH 2 NHCOPh) has a log D 7.4 two units greater than the parent compound.

20 Another approach to lower pK a of amines and make more lipophilic. Imine (Schiff base) prodrug anticonvulsant hydrolyze imine and amide to GABA inside brain

21 Thrombin inhibitor anticoagulant

22 SCHEME 9.3 Bioreductively activated carrier-linked prodrug

23 A water soluble prodrug of the anti-inflammatory drug valdecoxib (9.13) has been made (9.14).

24 iminesoximesketals Acetals or ketals can be made for rapid hydrolysis in the acidic medium of the GI tract.


26 Choice of hydrolytic prodrug group: The group must be stable enough in water for a shelf life of > 2 years (13 year half-life), but must be hydrolyzed in vivo with a half-life < 10 minutes. Prodrug Stability Properties Therefore, in vivo/in vitro lability ratio about 10 6.

27 poor water solubility corticosteroid for aqueous injection or opthalmic use Prodrug forms

28 To avoid formulation of etoposide with detergent, PEG, and EtOH (used to increase water solubility), it has been converted to the phosphate prodrug.

29 R = NH 2 -CH(R)-CO

30 corticosteroids - inflammation, allergic, pruritic skin conditions

31 Better absorption into cornea for the treatment of glaucoma The cornea has significant esterase activity

32 Bowel sterilant (administer rectally) Prodrug R = Ac (administered orally) Hydrolyzed in the intestines

33 The blood-brain barrier prevents hydrophilic molecules from entering the brain, unless actively transported. The anticonvulsant drug vigabatrin (see Chapter 5) crosses poorly. A glyceryl lipid (9.21, R = linolenoyl) containing one GABA ester and one vigabatrin ester was 300 times more potent in vivo than vigabatrin.

34 SCHEME 9.4 Liver metabolism of drugs containing phosphate and phosphonate moieties


36 Phosphatase should release the drug selectively in tumor cells. This approach has not been successful because the prodrugs are too polar, enzyme selectivity is not sufficient, or tumor cell perfusion rate is poor.

37 For selective activation of prodrugs in tumor cells Two steps: 1. incorporate a prodrug-activating enzyme into a target tumor cell 2. administer a nontoxic prodrug which is a substrate for the exogenous enzyme incorporated

38 1.The prodrug-activating enzyme is either nonhuman or a human protein expressed poorly 2. The prodrug-activating enzyme must have high catalytic activity 3. The prodrug must be a good substrate for the incorporated enzyme and not for other endogenous enzymes 4. The prodrug must be able to cross tumor cell membranes 5. The prodrug should have low cytotoxicity and the drug high cytotoxicity 6. The activated drug should be highly diffusable to kill neighboring nonexpressing cells (bystander killing effect) 7. The half-life of the active drug is long enough for bystander killing effect but short enough to avoid leaking out of tumor cells Criteria for Success with Enzyme-Prodrug Therapies

39 An approach for site-specific delivery of cancer drugs. Phase One: An antibody-enzyme conjugate is administered which binds to the surface of the tumor cells. The antibody used has been targeted for the particular tumor cell. The enzyme chosen for the conjugate is one that will be used to cleave the carrier group off of the prodrug administered in the next phase. Phase Two: After the antibody-enzyme has accumulated on the tumor cell and the excess conjugate is cleared from the blood and normal tissues, the prodrug is administered. The enzyme conjugated with the antibody at the tumor cell surface catalyzes the conversion of the prodrug to the drug when it reaches the tumor cell.

40 Advantages: 1. Increased selectivity for targeted cell 2. Each enzyme molecule converts many prodrug molecules 3. The released drug is at the site of action 4. Concentrates the drug at the site of action 5. Demonstrated to be effective at the clinical level Disadvantages: 1. Immunogenicity and rejection of antibody-enzyme conjugate 2. Complexity of the two-phase system and i.v. administration 3. Potential for leakback of the active drug

41 An example is carboxypeptidase G2 or alkaline phosphatase linked to an antibody to activate a nitrogen mustard prodrug. Humanization of antibodies minimizes immunogenicity. Note the prodrug-activating enzyme is a bacterial enzyme. SCHEME 9.5 Nitrogen mustard activation by carboxypeptidase G2 for use with ADEPT

42 Instead of using a prodrug-activating enzyme, a humanized prodrug-activating catalytic antibody (abzyme) can be used. Ideally, the abzyme catalyzes a reaction not known to occur in humans, so the only site where the prodrug could be activated is at the tumor cell where the abzyme is bound. Antibody 38C2 catalyzes sequential retro-aldol and retro-Michael reactions not catalyzed by any known human enzyme. Found to be long-lived in vivo, to activate prodrugs selectively, and to kill colon and prostate cancer cells.

43 SCHEME 9.6 Catalytic antibody 38C2 activation of a doxorubicin prodrug by tandem retro-aldol/retro-Michael reactions for use with ADAPT

44 A gene encoding the prodrug-activating enzyme is expressed in target cancer cells under the control of tumor-selective promoters or by viral transfection. These cells activate the prodrug as in ADEPT. SCHEME 9.7 Nitroreductase activation of a prodrug for use with GDEPT

45 Oral administration has lower bioavailability than i.v. injection. antihypertension plasma levels 8 times that with propranolol

46 R = Anthranilyl or acetylsalicyl

47 1. To reduce the number and frequency of doses 2. To eliminate night time administration 3. To minimize patient noncompliance 4. To eliminate peaks and valleys of fast release (relieve strain on cells) 5. To reduce toxic levels 6. To reduce GI side effects Long-chain fatty acid esters hydrolyze slowly Intramuscular injection is used also

48 Sedative/tranquilizer/antipsychotic slow release inject i.m. Antipsychotic activity for about 1 month

49 Activity about 1 month

50 t 1/2 about 9 h

51 Many of the prodrugs just discussed also have lower toxicity. For example, epinephrine (for glaucoma) has ocular and systemic side effects not found in dipivaloylepinephrine. Esters are prodrugs of aspirin

52 The antibacterial drug clindamycin (9.39) is bitter and not well tolerated by children. Clindamycin palmitate is not bitter. Either not soluble in saliva or does not bind to the bitter taste receptor or both.


54 Formaldehyde is a gas with a pungent odor that is used as a disinfectant. Too toxic for direct use. It is a stable solid that decomposes in aqueous acid. The pH of urine in the bladder is about 4.8, so methenamine is used as a urinary tract antiseptic. Has to be enteric coated to prevent hydrolysis in the stomach.


56 site specificity protection of drug from biodegradation minimization of side effects

57 To address these shortcomings, macromolecular drug delivery systems have been developed. A bipartate carrier-linked prodrug in which the drug is attached to a macromolecule, such as a synthetic polymer, protein, lectin, antibody, cell, etc. Absorption/distribution depends on the physicochemical properties of macromolecular carrier, not of the drug. Therefore, attain better targeting. Minimize interactions with other tissues or enzymes. Fewer metabolic problems; increased therapeutic index.

58 Macromolecules may not be well absorbed Alternative means of administration may be needed (injection) Immunogenicity problems

59 Synthetic polymers Aspirin linked to poly(vinyl alcohol) has about the same potency as aspirin, but less toxic.

60 9.44 shows a longer half life and longer anti-inflammatory activity

61 poly(methacrylate) to enhance water solubility testosterone No androgenic effect Polymer backbone may be sterically hindering the release of the testosterone.

62 A spacer arm was added, and it was as effective as testosterone. to enhance water solubility

63 poly(L-glutamine) spacer norethindrone - contraceptive Slow release over nine months in rats

64 Methotrexate attached to poly(L-lysine) showed increased uptake and overcame resistance

65 either hydrophilic or hydrophobic for site specificity

66 water-solubilizingantibody from rabbit antiserum against mouse lymphoma cells All 5 mice tested were alive and tumor free after 60 days (all controls died). Also, therapeutic index greatly enhanced (40 fold). spacer arm poly(L-Glu)

67 Tumor cells take up proteins rapidly. Proteins broken down inside cells, releasing the drug. Shown to inhibit growth of Ectomelia virus in mouse liver, whereas free inhibitor did not. Drug attached to albumin (R = albumin) antitumor

68 calicheamicin, except as disulfide instead of trisulfide spacerhumanized Withdrawn due to release of calicheamicin nonenzymatically. Exhibits no immune response. SCHEME 9.8 Antibody-targeted chemotherapy, a prodrug for calicheamicin

69 FIGURE 9.1 (A) Brentuximab vedotin, the first antibody-drug conjugate with a more stable linker; (B) Trastuzumab emtansine, the second antobody-drug conjugate approved

70 A bipartate prodrug may be ineffective because the linkage is too labile or too stable. In a tripartate prodrug, the carrier is not attached to the drug; rather, to the linker. Therefore, more flexibility in the types of functional groups and linkages that can be used, and it moves the cleavage site away from the carrier. The linker-drug bond must cleave spontaneously (i.e., be self-immolative) after the carrier-linker bond is broken.

71 SCHEME 9.9 Tripartite prodrugs

72 SCHEME 9.10 Double prodrug concept

73 antibacterial Various esters made were too stable in humans (although they were hydrolyzed in rodents) - thought the thiazolidine ring sterically hindered the esterase. Poor oral absorption (40%) Excess antibiotic may destroy important intestinal bacteria used in digestion and for biosynthesis of cofactors. Also, more rapid onset of resistance.

74 98-99% absorbed Ampicillin is released in < 15 minutes SCHEME 9.11 Tripartite prodrugs of ampicillin

75 hydrolysis deactivated hydrolysis activated hydrophilic drug electron-donating, lipophilic carrier electron- withdrawing; hydrophilic Passive diffusion of 8.47 into the brain; active transport of 8.49 out of the brain If oxidation occurs before it gets into the brain, it cannot cross the blood-brain barrier. XH of the drug is NH 2, OH, or COOH SCHEME 9.12 Redox drug delivery system to cross the blood–brain barrier

76 When the drug is a carboxylic acid, a self- immolative reaction also can be used. SCHEME 9.13 Redox tripartite drug delivery system

77  -Lactams are too hydrophilic to cross the blood-brain barrier effectively. High concentrations of  -lactams delivered into brain. SCHEME 9.14 Redox tripartite drug delivery of β-lactam antibiotics

78 Permeases are bacterial transport proteins for uptake of peptides. Only L,L-dipeptides are active SCHEME 9.15 Activation of peptidyl derivatives of 5-fluorouracil

79 SCHEME 9.16 Tripartite macromolecular drug delivery system This has been applied to daunorubicin

80 A bipartate or tripartate prodrug in which the carrier is a synergistic drug with the drug to which it is linked. Antibacterial ampicillin  -lactamase inactivator penicillanic acid sulfone Hydrolysis gives 1:1:1 ampicillin : penicillanic acid sulfone : formaldehyde

81 Well absorbed Both components are released together and quantitatively after absorption Maximal effect of the combination of the two drugs occurs at 1:1 ratio Distribution/elimination of components are similar

82 Carrier-linked prodrugs largely use hydrolytic activation Bioprecursor drugs mostly use oxidative or reductive activation The metabolically-activated alkylating agents discussed in Chapter 6 are actually examples of bioprecursor prodrugs.

83 Cimetidine and ranitidine (Chapter 3) reduce gastric acid secretion by antagonizing the H 2 histamine receptor. Another way to lower gastric acid secretion is by inhibition of the enzyme H +,K + -ATPase (also called the proton pump), which exchanges protons for potassium ions in parietal stomach cells, thereby increasing stomach acidity.

84 Lead compound found in a random screen. Liver toxicity observed thought to be because of the thioamide group.

85 Related analogs made, and 9.72 had good antisecretory activity. Modification gave 9.73 with high activity. The sulfoxide (9.74) was more potent, but it blocked iodine uptake into the thyroid.

86 Modification of 9.74 gave 9.75 having no iodine blockage activity. Picoprazole shown to be an inhibitor of H +,K + -ATPase. SAR of analogs indicated electron-donating groups on the pyridine ring were favorable. Increased inhibition of H +,K + -ATPase. Best analog was omeprazole (9.76).

87 The pK a of the pyridine ring of omeprazole is about 4, so it is not protonated and able to cross the secretory canaliculus of the parietal cell. The pH inside the cell is below 1, so this initiates the protonation reaction below. Formation of 9.77 leads to covalent attachment. Omeprazole also inhibits isozymes of carbonic anhydrase, another mechanism for lowering gastric acid secretion. SCHEME 9.17 Mechanism of inactivation of H +,K + -ATPase by omeprazole


89 Hydrolysis can be a mechanism for bioprecursor prodrug activation, if the product requires additional activation. antitumor agentprodrugs of leinamycin SCHEME 9.18 Conversion of leinamycin into a series of prodrugs

90 Hydrolysis of these analogs gives an intermediate that reacts further to the activated form. increased stability over leinamycin this was synthesized and gave 9.85 as well as DNA cleavage SCHEME 9.19 Hydrolytic activation of leinamycin prodrugs

91 potent inhibitor of dihydroorotate dehydrogenase rheumatoid arthritis drug Inhibition of dihydroorotate dehydrogenase blocks pyrimidine biosynthesis in human T lymphocytes. SCHEME 9.20 Activation of leflunomide to the active drug

92 SCHEME 9.21 Bioprecursor prodrugs for alprazolam and triazolam

93 Analgesic activity of phenacetin is a result of O-dealkylation to acetaminophen.

94 Neoplastic (cancer) cells have a high concentration of phosphoramidases, so hundreds of phosphamide analogs of nitrogen mustards were made for selective activation in these cells. Cyclophosphamide was very effective, but it required liver homogenates (contains P450) for activation. Therefore oxidation is required, not hydrolysis. isolated SCHEME 9.22 Cytochrome P450- catalyzed activation of cyclophosphamide

95 identified advanced Hodgkin’s disease SCHEME 9.23 Cytochrome P450-catalyzed activation of procarbazine

96 Pralidoxime chloride is an antidote for nerve poisons. It reacts with acetylcholinesterase that has been inactivated by organophosphorus toxins.

97 To increase the permeability of pralidoxime into the CNS, the pyridinium ring was reduced (9.103). oxidation in brain Similar to the reversible redox drug delivery strategy for getting drugs into the brain by attaching them to a dihydronicotinic acid, hydrophobic crosses the blood-brain barrier; oxidation to prevents efflux from brain.

98 SCHEME 9.24 Acetylcholinesterase-catalyzed hydrolysis of acetylcholine

99 SCHEME 9.25 Phosphorylation of acetylcholinesterase by diisopropyl phosphorofluoridate affinity labeling agent irreversible inhibition Inactivation prevents degradation of the excitatory neurotransmitter acetylcholine. Accumulation of acetylcholine causes muscle cells in airways to contract and secrete mucous, then muscles become paralyzed.

100 SCHEME 9.26 Reactivation of phosphorylated acetylcholinesterase by pralidoxime chloride

101 Temporary inhibition of acetylcholinesterase enhances cholinergic action on skeletal muscle. Used for the neuromuscular disease myasthenia gravis covalent, but reversible inhibition SCHEME 9.27 Carbamylation of acetylcholinesterase by neostigmine

102 Reversible (noncovalent) inhibitors of acetylcholinesterase, such as donepezil and tacrine are used for Alzheimer’s disease. Enhances neurotransmission involved in memory.

103 S-oxidation of clopidogrel SCHEME 9.28 S-Oxidation of clopidogrel, which initiates its inactivation of P2Y 12 anticoagulant

104 aromatic hydroxylation oxidation next to sp 2 carbonyl SCHEME 9.29 Cytochrome P450-catalyzed conversion of a cyclohexenone to a catechol

105 active anticonvulsant agent

106 Stimulation of pyruvate dehydrogenase results in a change of myocardial metabolism from fatty acid to glucose utilization. Glucose metabolism requires less O 2 consumption. Therefore, utilization of glucose metabolism would be beneficial to patients with ischemic heart disease (arterial blood flow blocked; less O 2 available).

107 Oxfenicine (8.105, R = OH) is actively transported and is transaminated (a PLP aminotransferase) in the heart to (R = OH). Arylglyoxylic acids (8.104) stimulate pyruvate dehydrogenase, but have a short duration of action.

108 ulcerative colitis For inflammatory bowel disease Causes side effects Anaerobic cleavage by bacteria in lower bowel SCHEME 9.30 Reductive activation of sulfasalazine

109 To prevent side effect by sulfapyridine a macromolecular delivery system was developed. poly(vinylamine) spacer Not absorbed or metabolized in small intestine. Released by reduction at the disease site. Sulfapyridine is not released (still attached to polymer). More potent than sulfasalazine.

110 antiviral drug Vidarabine is rapidly deaminated by adenosine deaminase , R = N 3 is not a substrate for adenosine deaminase and also can cross the blood-brain barrier for brain infections.

111 anti-arthritis Sulindac is inactive in vitro; the sulfide is active in vitro and in vivo.

112 Sulindac is an indane isostere of indomethacin, which was designed as a serotonin analog. The 5-F replaced the 5-OMe group to increase analgesic properties. The p-SOCH 3 group replaced p-Cl to increase water solubility.

113 To increase the lipophilicity of thiamin for absorption into the CNS. nonenzymatic poorly absorbed into CNS SCHEME 9.31 Conversion of thiamin tetrahydrofurfuryl disulfide to thiamin

114 antimalarial, toxic To diminish toxicity of primaquine and target it for cells with the malaria parasite, a macromolecular drug delivery system was designed. primaquine Intracellular thiol much higher than in blood; selective reduction inside the cell for improved uptake in liver Therapeutic index of is 12 times higher than in mice.

115 SCHEME 9.32 Reductive activation of ronidazole

116 SCHEME 9.33 Phosphoramidite-based prodrug for intracellular delivery of nucleotides

117 Anti-leukemia drug Inhibits several enzymes in the purine nucleotide biosynthesis pathway. SCHEME 9.34 Nucleotide activation of 6-mercaptopurine

118 antiviral 2-deoxyguanosine Resembles structure of 2-deoxyguanosine R = PO 3 = viral guanylate kinase viral thymidine kinase R = P 2 O 6 3- viral phosphoglycerate kinase R = P 3 O 9 4- Uninfected cells do not phosphorylate acyclovir (selective toxicity)

119 Acyclovir triphosphate is a substrate for viral  -DNA polymerase but not for normal  -DNA polymerase Incorporation into viral DNA leads to a dead-end complex (not active). Disrupts viral replication cycle and destroys the virus. Even if the triphosphate of acyclovir were released, it is too polar to be taken up by normal cells. High selective toxicity

120 Modification of thymidine kinase Change in substrate specificity for thymidine kinase Altered viral  -DNA polymerase

121 Hydrolyzes here Only 15-20% of acyclovir is absorbed Therefore, prodrugs have been designed to increase oral absorption. Prodrug for a prodrug adenosine deaminase acyclovir

122 Hydroxylates here acyclovir xanthine oxidase This prodrug is 18 times more water soluble than acyclovir.

123 A bipartate carrier-linked prodrug of acyclovir, the L-valyl ester of acyclovir, has 3-5 fold higher oral bioavailability with the same safety profile.

124 An analog of acyclovir whose structure is even closer to that of 2-deoxyguanosine is ganciclovir. More potent than acyclovir against human cytomegalovirus.

125 C in place of O Two carbon isosteres of ganciclovir are available. C in place of O Better oral absorption than penciclovir Converted to penciclovir rapidly

126 Activity of minoxidil requires sulfotransferase-catalyzed sulfation to minoxidil sulfate. Inhibitors of the sulfotransferase inhibit the activity of minoxidil, but not minoxidil sulfate. hair growth

127 An imbalance in the inhibitory neurotransmitter dopamine and the excitatory neurotransmitter acetylcholine produces movement disorders, e.g. Parkinson’s disease. In Parkinson’s there is a loss of dopaminergic neurons and a low dopamine concentration. Dopamine treatment does not work because it cannot cross blood-brain barrier, but there is an active transport system for L-dopa (levodopa, 8.133, R = COOH).

128 After crossing blood- brain barrier L-aromatic amino acid decarboxylase (PLP) dopamine (R = H) Does not reverse the disease, only slows progression.

129 Monoamine oxidase B (MAO B) degrades dopamine in the brain. Therefore, a MAO B-selective inactivator is used to protect the dopamine - selegiline (L-deprenyl). Peripheral L-aromatic amino acid decarboxylase destroys >95% of the L-dopa in the first pass. Maybe only 1% actually gets into brain.

130 To protect L-dopa from peripheral (but not CNS) degradation, inhibit peripheral L-aromatic amino acid decarboxylase with a charged molecule that does not cross the blood-brain barrier. (used in U.S.) Selectively inhibits peripheral L-amino acid decarboxylase. The dose of L-dopa can be reduced by 75%. (used in Europe and Canada)

131 Earlier we found that inactivation of brain MAO A has an antidepressant effect, but a cardiovascular side effect occurs from inactivation of peripheral MAO A (R = COOH) is actively transported into the brain, where L-aromatic amino acid decarboxylase converts it to (R = H), a selective MAO A mechanism-based inactivator. Carbidopa protects (R = COOH) from decarboxylation outside of the brain.

132 Dopamine increases renal blood flow. Prodrugs were designed for selective renal vasodilation. L-  -glutamyl-L-dopa Dopamine accumulates in the kidneys because of high concentrations of L-  -glutamyltranspeptidase and L-aromatic amino acid decarboxylase there. L-dopa Example of a carrier-linked prodrug of a bioprecursor prodrug for dopamine. SCHEME 9.35 Metabolic activation of L -γ-glutamyl- L -dopa to dopamine

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