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By E. Denpok. New Saint Andrews College.

It can make up to 10% of the dry weight of the juice and is responsible for the bitter taste buy viagra jelly now yellow 5 impotence. Additional studies confirmed the ability of these flavonoids to inhibit 3A4 specific activities discount viagra jelly master card erectile dysfunction drug companies, including nifedipine oxidation (334) generic viagra jelly 100 mg with visa impotence due to diabetes, midazolam a-hydroxy- lation (37 generic viagra jelly 100mg with amex erectile dysfunction under 30,335), quinidine 3-hydroxylation (335), 17b-estradiol metabolism (336), and saquinavir metabolism (337). Two clinical studies examined the relative inhibitory action of quercetin vs grapefruit juice on nifedipine pharmacokinetics (338) and narin- gen vs grapefruit juice on felodipine pharmacokinetics (339). Neither flavoniod when administered at doses comparable to those in the grapefruit juice caused any effect on the bioavailability of the drug (338,339). Their inhibitory capacity for 3A4-related substrates was one to two orders of magnitude greater than the flavonoids (Fig. The relative potency of components of grapefruit juice to inhibit P450 3A4 activities. The data for the flavonoids are for nifedipine oxidation and are from Guengerich and Kim (333). With only limited amounts of the furanocoumarins available, there has not yet been a clinical study to indicate they can substitute for grapefruit juice in causing drug inter- actions. Their role in grapefruit juice drug interactions therefore has not yet been established. Grapefruit juice also effects P-glycoprotein-mediated transport, increas- ing the basolateral to apical flux (337,346,347). The relative role the transporter and P450 3A4 have on the bioavailability of a drug may also be important in determining the active component in the effect of grapefruit juice. For benzodiazepines undergoing oxidative metabolism, P450 3A4 appears to be more important. In normal subjects, the effect was modest, and accompanied with no or only minor effects on the pharmacodynamics of the benzodiazepines (348,350–352). This suggests that cirrhotics are more dependent upon intestinal metabolism of midazolam. In a study on other juices, tangerine juice was found to delay the absoprtion of midazolam and slightly delay its pharmacodynamic effects (353; Table 29). Interactions with Miscellaneous Agents Clinical studies concerning potential drug interactions with benzodiazepines have been performed with a number of drugs for which either only a single drug in its class was studied, or there was no explicit connection with an aspect of drug metabolism. It did produce a significant decrease in the pharmacodynamic measures of diazepam (354; Table 30). The effect of chronic theophylline on alprazolam was compared in subjects with chronic obstructive pul- monary disease that were or were not taking theophylline. Caffeine was found to have no effect on the pharmacokinetics of diazepam (356) or alprazolam (203); but caffeine did slightly diminsh the pharmaco- dynamic measures for diazepam (356; Table 30). Chronic disulfiram treatment was found to diminsh the elimination of chlordiazepoxide and diazepam, but not that of oxazepam in normal subjects (Table 30). The clearance and t1/2 of the three benzodiazepines in chronic alcoholics who had received chronic disul- firam treatment were similar to those in the disulfirma-treated normal subjects (358). In a study with 11 chronic alcoholics, alprazolam was given prior to initiation of disul- firam treatment and again after 2 wk of disulfiram; no change in the pharmacokinetics of alprazolam was noted (359). Like oxaze- pam it is primarily elimated after glucuronidation, and both are highly protein bound. When oxazepam was given before and after 7 d of 2/d treatment with diflunisal, the Cmax of oxazepam was decreased and its oral clearance increased. The authors conclude that the interaction resulted from the displacement of oxazepam from its protein-binding sites and by inhibition of the tubu- lar secretion of the oxazepam glucuronide. The authors concluded that these find- ings were consistent with the induction of P450 and/or glucuronidation (360). Five daily “small” doses of dexamethasone were found to have no significant effect on the pharma- cokinetics or pharmacodynamics of triazolam in normal volunteers (361; Table 30). The authors did detect a significant decrease in the percentage of diazepam plus metab- olites excreted in urine over a 96-h period (362). The findings suggest that paracetamol may decrease the glucuronidation of diazepam metabolites. The effect of probenecid on the elimination of benzodiazepines was first studied 1. Drug Interactions with Benzodiazepines 65 Table 31 Key to Drug Interaction Tables Interacting drug The route is oral, unless stated otherwise. An indication of the duration of treament is given, and when different the benzodiazepines considered are noted separately in parentheses (e. Benzodiazepines The benzodiazepine of interest is indented 1/4 inch; if a metabolite was also studied, it is listed directly below with a 1/2-inch indentation. The abbreviations for route of administration are: or, oral; iv, intravenous; im, intramuscular. N For cross-over studies only one group of subject numbers are provided; if gender was specified, females are noted with an “f”; males with an “m” (e. For comparisons between groups, a ‘/’ separates the groups; the one receiving the interactant is listed first (50/40, refers to a study where 50 subjects recieved the interactant and 40 did not). Pharmacokinetics Are presented as the ratio of the interactant to the control group. Cl Clearance for iv administration; apparent oral clearance for oral administration. PhDyn qualitative assessment of the results of pharmacodynamic measures recorded in the study. This was both an assessment of the degree of change and the number of measures that changed: 0 – no effect; - to ----, a dimunition in the pharmacodynamics ranging from slight to loss of all effect; + to ++++, an enhancement of the pharmacodynamics ranging from slight to toxic. The t1/2 of lorazepam was significantly increased and its clearance significantly decreased. This result suggested not just inhibition of ex- cretion, but also inhibition of glucuronide formation (363). With temazepam there was no significant effect on plasma pharma- cokinetics, but there was reduced urinary content of the temazepam glucuronide (300). This was associated with potentiation of the psychomotor effects of the benzodiaz- epine (Table 30). The authors suggest that the major effect is on the elimination of the metabolite (364). Probenecid does effect the renal elimination of many benzodiazepines; it may also have an effect on glucuronidation and possibly P450 mediated reactions. The effect of modafinal on the pharmacokintics of triazolam (and ethinyl estradiol) was studied in females taking daily birth control medication con- taining ethinyl estradiol (366). In a group of woman given triazolam before and after 28 d of treatment with modafinal, there was a significant induction of the elimination of triazolam (Table 30). John’s wort, garlic oil, Panax ginseng, Ginkgo biloba) on a P450 phe- notyping “cocktail” designed to measure 1A2, 2D6, 2E1, and 3A4 activities. Individuals had the phenotyping cocktail before and after a 28-d period of use of the supplement; each supplement use was separated by a 30-d washout period. When an inhibition of metabolism is also encountered, the effect may be synergistic. Interactions with other drugs and dietary substances are generally based upon an interaction at the site of metabolism. Most often this reflects the involvement of P450 3A4, but in some instances the involvement of 2C19 in diazepam metabolism, and glucuronidation are also sites of interaction. A few examples of displacement from protein binding and inhibition of renal tubular secre- tion also exist. These metabolic interactions can vary from having little or no effect on the pharmacodynamics to inhibitions that produce toxic side effects and inductions that essentially negate the pharmacodynamics of the benzodiazepine. A misadventure with either or both interactant is likely to magnify the end result. Though I have tried to achieve a thorough review of the peer-reviewed literature, many papers were not 1. Authors who feel I have missed their studies are asked to send the pertinent reprints. Should this article be updated in the future, I will make my best effort to include those studies at that time. Adinazolam pharmacokinetics and behavioral effects fol- lowing administration of 20–60 mg doses of its mesylate salt in volunteers. Enantiomer resolution of camazepam and its derivatives and enantio- selective metabolism of camazepam by human liver microsomes. Investigation of the metabolites of tofizopam in man and animals by gas-liquid chromatography-mass spectrometry. In vitro methods for assessing human drug metabolism: their use in drug development. Use of in vivo human metabolism studies in drug development: an indus- trial perspective. The use of heterologously expressed drug metabolizing enzymes —state of the art and prospects for the future. Cytochrome P450 inhibitors: evaluation of speci- ficities in the in vitro metabolism of therapeutic agents by human liver microsomes. Correlations among changes in hep- atic microsomal components after intoxication with alkyl halides. Prediction of human liver microsomal oxida- tions of 7-ethoxycoumarin and chlorzoxazone with kinetic parameters of recombinant cyto- chrome P-450 enzymes. Eight inhibitory monoclonal antibodies define the role of individual P-450s in human liver microsomal diazepam, 7-eth- oxycoumarin, and imipramine metabolism. Use of inhibitory mono- clonal antibodies to assess the contribution of cytochromes P450 to human drug metabo- lism.

Talinolol order viagra jelly 100 mg erectile dysfunction drugs list, a good P-gp substrate generic 100 mg viagra jelly with amex erectile dysfunction treatment with fruits, is eliminated from the body mainly by intestinal and renal excretion with minimal metabolism in humans buy discount viagra jelly 100 mg online erectile dysfunction and diabetes pdf. In a clinical study order discount viagra jelly line impotence meaning, a P-gp-mediated interaction between talinolol and verapamil has been reported (45). The inhibitory effect of verapamil on the intestinal secretion of talinolol was determined in six healthy volunteers by using the intestinal per- fusion technique. While perfusing the small intestine with a verapamil-free solution, the mean intestinal secretion rate of talinolol was 4. Similar to the clinical data, talinolol-verapamil interaction was also observed in rats. A major challenge in the therapeutic treatment of cancer is the so-called multidrug resistance to anticancer drugs. Because over expression of P-gp has often been observed in tumor biopsies, it is believed that P-gp is one of the major factors responsible for the drug resistance, and inhibition of P-gp function may increase the sensitivity of cancer cells to anticancer drugs. In addition to transporter inhibition, drug interactions caused by transporter induction have also been reported. In a clinical study, the pharmacokinetics of digoxin before coad- ministration of rifampicin (600 mg/day for 10 days) was compared with those after rifampicin treatment in eight healthy volunteers. In this study, duodenal biopsies were obtained from each volunteer before and after admin- istration of rifampicin. Taken together, these results strongly suggest that the digoxin-rifampicin interaction was mediated mainly by P-gp induction. This means that the decreased plasma concentration of digoxin during rifampicin treatment is caused by a combination of reduced bioavailability of digoxin as a result of P-gp induction. The inductive effect of rifampicin on the pharmacokinetics of talinolol, which is eliminated from the body predominantly by renal and intestinal excretion with minimal metabolism (<1. On the other hand, the total clearance of talinolol was increased sig- nificantly by 30% after intravenous administration of the drug during rifampicin treatment. In addition, treatment with rifampicin resulted in a significant increase in the expression of duodenal P-gp content by about fourfold in these volunteers (28). The duodenal P-gp expression correlated significantly with the total clearance of talinolol. Since talinolol undergoes minimal metabolism, these results clearly demonstrated that the observed talinolol-rifampicin interaction was attributed mainly to a combination of a decrease in absorption and an increase in elimination via the induction of P-gp. In conclusion, direct evidence of transporter-mediated drug interaction can be obtained relatively readily if a transporter substrate, such as digoxin or tali- nolol, undergoes minimal metabolism. In many cases, a transporter-mediated drug interaction was postulated simply on the basis of circumstantial evidence. In a clinical study, plasma concentrations of cerivastatin were determined after oral administration of 0. Together with the observation that the volume of distribution (Vc/F) appeared to be lower in the transplant patients compared with that in normal volunteers, they concluded that the cerivastatin-cyclosporine interaction is transporter mediated because of the inhibition of liver transport processes of cerivastatin by cyclosporine (53). Unfortunately, their conclusion is based on speculation without any supporting data. To explore the underlying mechanisms for the cerivastatin-cyclosporine interaction, Shitara et al. A significant increase in plasma concentrations of pravastatin has also been reported when coadministered with gemfibrozil (58). After intrave- nous administration of radiolabeled pravastatin to healthy volunteers, approxi- mately 47% of total body clearance was via renal excretion and 53% by nonrenal routes, namely biliary excretion (59). Since gemfibrozil reduced the renal clearance of pravastatin by twofold, it is clear that the pravastatin-gemfibrozil interaction is due at least partly to the inhibition of renal transporters. However, the identities of the renal transporters have not been well characterized. In addition, gemfibrozil could also inhibit the hepatic transporters of pravastatin since biliary excretion is also a major route of pravastatin elimination. Therefore, the underlying mechanisms for the pravastatin-gemfibrozil interaction are still not fully understood. Ambiguity also exists in the interpretation of the underlying mechanisms for the fexofenadine-rifampicin interaction. Pretreatment of rifampicin significantly decreased the systemic exposure of fexofenadine (a good P-gp substrate) in healthy volunteers (60). On the basis of the assumption that fexofenadine 556 Lin undergoes minimal metabolism in humans, the investigators concluded that the decreased plasma concentrations were the result of a reduced bioavailability caused by induction of intestinal P-gp. The assumption that fexofenadine is metabolized only to a minor extent in humans came originally from an abstract (61). In the abstract, it was stated that approximately 80% and 11% of an oral 14 dose of [ C]fexofenadine was recovered in the feces and urine, respectively, in a mass balance study in humans. However, it is unknown if the fecal component represents unabsorbed drug or the result of biliary and intestinal excretion. If the fraction of fexofenadine absorbed from the intestine is low (in the range of 10%) or if metabolites account for a significant fraction of radioactivity in the feces, the assumption that fexofenadine is subject to minimal metabolism in humans may not be valid. Similarly, the interpretation of the mechanism of the grapefruit juice– fexofenadine interaction may not necessarily be reasonable. In a clinical study, grapefruit juice or water at a volume of ‘‘1200 mL’’ was ingested within three hour after oral administration of 120-mg fexofenadine in a crossover study in 10 healthy subjects (63). Ingestion of such an unusually large volume of grapefruit juice (1200 mL within 3 hour after drug dosing) may alter intestinal pH, osmolarity, gastric emptying time, and intestinal transit time of fexofenadine. Therefore, it is arguable that changes in Transporter-Mediated Drug Interactions 557 gastrointestinal physiology may have indirect effects on the oral absorption of fexofenadine. Because of the possible effects of the large volume of grapefruit juice on the gastrointestinal physiology, these investigators subsequently conducted a clinical study to evaluate the inhibitory effect of grapefruit juice on the absorption kinetics of fexofenadine at a more reasonable volume (300 mL) of grapefruit juice (65). These results support the argument that a large volume of grapefruit juice could cause significant changes in gastrointestinal physiology and thereby complicate data interpretation. The Ki value of ketoconazole to inhibit the metabolism of midazolam in human liver microsomes was determined to be 0. These results strongly suggest that ketoconazole may also have a significant effect on the function of P-gp. The pharmaco- kinetics of cyclosporine were studied in six healthy volunteers after oral and intravenous administration of the drug before and after rifampicin pretreatment (600 mg/day for 11 days). Blood clearance of cyclosporine increased from 5 mL/min/kg before rifampicin treatment to 7 mL/min/kg during rifampicin treatment, while the bioavailability decreased from 27% before rifampicin treatment to 10% after rifampicin treatment. Rifampicin not only increased the elimination clearance of cyclosporine but also decreased its bioavailability to a greater extent than would have been predicted by the increased clearance. As the examples cited above indicate, many clinical drug interactions have been considered to be mediated by inhibition or induction of transporters based only on circumstantial evidence. Therefore, care should be taken when exploring the underlying mechanism of drug interactions. However, from animal studies it becomes evident that the changes in tissue (intracellular) concentrations of drugs caused by inhibition of transporters are 560 Lin much greater than the corresponding changes in plasma concentrations. The concentrations of digoxin and saquinavir in the wild-type [mdr1a/1b(þ/þ)] fetus were increased to levels that were comparable to that in the mdr1a/1b(À/À) fetus after oral coadministration of the P-gp inhibitors to heterozygous mothers (75). The notion that inhibition of trans- porters has a much greater impact on the distribution of drugs into tissues than on plasma concentrations is further supported by studies with transporter-deficient (transgenic) mice. For example, the digoxin concentration in brain were about 28-fold higher in mdr1a/1b(À/À) mice compared with those in wild-type mice, while there was only a 2. One important lesson learned from these animal studies is that transporter inhibition has a much greater impact on the tissue distribution of drugs, par- ticularly with regard to the brain, than on the systemic exposure of drugs. Hence, the potential risk of transporter-mediated drug interactions might be under- estimated if only plasma concentration is monitored. Therefore, one should carefully assess the potential risk of transporter-mediated drug interactions when potent transporter inhibitors are administered together. With recent advances in molecular biology and biotechnology, the number of documented transporters continues to grow in an exponential manner, although the majority of the newly identified transporters are still not fully characterized. Therefore, there is a long way to go before we can fully understand the physiological function of all the drug transporters and their interplay in relation to drug absorption and disposition. Transporter-Mediated Drug Interactions 561 The molecular complexity of transporter inhibition and induction impairs our ability to predict the potential role of transporter-mediated drug-drug inter- actions, either in a quantitative or qualitative sense. Another important lesson learned from animal studies is that transporter inhi- bition has a much greater impact on the tissue distribution of drugs, particularly with regard to the brain, than on the systemic exposure of drugs measured in plasma. The potential risk of transporter-mediated drug interactions might be underestimated if only plasma concentrations are monitored. Therefore, one should carefully assess the potential risk of transporter-mediated drug inter- actions when potent inhibitors of transporters are administrated. Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport. Azidopine noncompetitively interacts with vinblastine and cyclosporin A binding to P-glycoprotein in multidrug resistant cells. Human P-glycoprotein exhibits reduced affinity for substrates during a catalytic transition state. Substrate-induced conformational changes in the transmembrane segments of human P-glycoprotein. Simultaneous binding of two different drugs in the binding pocket of the human multidrug resistance P-glycoprotein. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Altered localization and activity of canalicular Mrp2b in estradiol-17-b-D-glucuronide-induced cholestasis. Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug-drug interaction.

The importance of this design consideration follows a 1968 Australasian outbreak of phenytoin drug toxicity caused by the replacement of an excipient in a marketed formulation of an anti- seizure drug called phenytoin; the new excipient chemically interacted with the phenytoin drug molecule cheap viagra jelly 100 mg on-line impotence ginseng, ultimately producing toxicity viagra jelly 100 mg discount erectile dysfunction drugs without side effects. This phase covers the time duration from the point of the drug’s absorption into the body until it reaches the microenvironment of the receptor site trusted 100mg viagra jelly icd 9 code for erectile dysfunction due to medication. During the pharmacokinetic phase cheap viagra jelly online mastercard impotence at 40, the drug is transported to its target organ and to every other organ in the body. In fact, once absorbed into the bloodstream, the drug is rapidly transported throughout the body and will have reached every organ in the body within four minutes. Since the drug is widely distributed throughout the body, only a very small fraction of the administered compound ultimately reaches the desired target organ—a significant problem for the drug designer. The magnitude of this problem can be appreciated by the following simple calculation. A typical drug has a molecular weight of approximately 200 and is administered in a dose of approximately 1 mg; thus, 1018 molecules are administered. The human body contains almost 1014 cells, with each cell containing at least 1010 molecules. Therefore, each single administered exogenous drug molecule confronts some 106 endogenous molecules as potential available receptor sites—the proverbial “one chance in a million. While being transported in the blood, the drug molecule may be bound to blood proteins. Highly lipophilic drugs do not dissolve well in the aqueous serum and thus will be highly protein bound for purposes of transport. If a person is taking more than one drug, various drugs may compete with each other for sites on the serum proteins. During this transport process, the drug is exposed to metabolic transformations that may chemically alter the integrity of its chemical structure. In fact, some drug molecules are com- pletely transformed to biologically inactive metabolites during their first pass through the liver; this is the so-called first pass effect. Due to the anatomical arrangement of blood vessels in the abdomen, all orally administered drugs must immediately pass through the liver follow- ing absorption from the small intestine. Accordingly, a drug molecule that is susceptible to a first pass effect should in theory be designed and formulated in a manner that mini- mizes small intestine absorption. One method of reducing a first pass effect is to admin- ister the drug sublingually so that it is absorbed under the tongue and has an opportunity of avoiding the initial pass through the liver. Like the liver, the kidney is another organ system that may influence the effectiveness of a drug molecule during the pharmacokinetic phase. Such molecules have short half-lives (the period of time during which one-half of the drug molecules is excreted). A short half-life reduces the effectiveness of a drug molecule because it shortens the time duration available to the drug for distribution and binding to its receptor. In addition, as a general rule, a drug is administered at least once every half-life; a drug with a half-life of 24 hours may be administered once per day whereas a drug with a 12 h half-life must be given at least twice per day. If a drug has a half-life of 20 minutes it would be impractical to administer it three times per hour. The final impediment to drug molecule effectiveness during the pharmacokinetic phase is the existence of barriers. In order to reach its target organ, the drug molecule must traverse a variety of membranes and barriers. This is particularly true if the drug is destined to enter the brain, which is guarded by the blood–brain barrier. This is a lipid barrier composed of endothelial tight junctions and astrocytic processes. This design feature is highly desirable if one wishes to develop drug molecules for non-neurologic indications that will have no neurologic side effects. On the other hand, the existence of the blood–brain barrier must be explicitly consid- ered when designing drugs for neurological indications. Different organ systems inflict varying degrees of assault on the integrity of the drug molecule during its journey to the receptor. Once the drug molecule has entered the region of its receptor, it is in the pharmacodynamic phase. During this phase, the molecule binds to its receptor through the complementarities of their mole- cular geometries. The functional groups of the drug molecule interact with correspond- ing functional groups of the receptor macromolecule via a variety of interactions, including ion–ion, ion–dipole, dipole–dipole, aromatic–aromatic, and hydrogen bond- ing interactions. The binding of the drug molecule to its receptor enables the desired biological response to occur. C l i n i c a l P h a r m a c o l o g y a n d D r u g T h e r a p y , 3 r d E d n. The three-dimensional arrangement of atoms within a drug molecule that permits a specific binding interaction with a desired recep- tor is called the pharmacophore. The atoms that constitute the pharmacophore are a subset of all the atoms within the drug molecule. The pharmacophore is the bioactive face of the molecule and is that portion of the molecule that establishes intermolecular interactions with the receptor site. A pharmacophore is the assembly of geometric and electronic features required by a drug molecule to ensure both an optimal supramolecular interaction with its target receptor and the elicitation of a biological response. The term pharmacophore does not represent a single real molecule but a portion of a molecule. It is incorrect to name a structural skeleton, such as a phenothiazine or a prostaglandin, as a pharma- cophore. It is correct, however, to regard a pharmacophore as the common structural denominator shared by a set of bioactive molecules; the pharmacophore accounts for the shared molecular interaction capabilities of a group of structurally diverse drug molecules toward a common target receptor. For example, one bioactive face of acetylcholine permits interaction with a muscarinic receptor, while another bioactive face of acetylcholine permits interaction with a nicotinic receptor (section 4. The other portions of the drug molecule that are not part of the pharmacophore constitute molecular baggage. The role of this molecular baggage is to hold the func- tional group atoms of the pharmacophore in a fixed geometric arrangement (with minimal conformational flexibility) to permit a specific receptor interaction while minimizing both interactions with toxicity-mediating receptors and the metabolic (via liver) and rapid excretion (via kidney) problems associated with the pharmaco- kinetic phase. Two other less frequently discussed fragments of a drug molecule are the toxicophore and the metabophore. If a drug molecule has multiple toxicities arising from several undesirable interactions, then it may possess more than one toxicophore. From the perspective of drug design, if a toxicophore does not overlap with the pharmacophore in a given drug molecule, then it may be pos- sible to redesign the molecule to eliminate the toxicity. However, if the pharmacophore and toxicophore are congruent molecular fragments, then the toxicity is inseparable from the desired pharmacological properties. The bioactive face is the portion of the drug molecule that interacts with the receptor; the remainder of the molecule, called molecular baggage, holds the bioactive face in a desired geometry. The pharmacophore is the arrangement of mole- cules that permits the bioactive face to interact with the receptor. The toxicophore is the fragment that is responsible for toxicity; the metabophore is the fragment that is responsible for metabolism. If these various fragments are separate (as in B), then toxicity can be “designed out of the drug molecule”; if they overlap (as in C), then it may be impossible to separate the toxicophore from the pharmacophore. It is sometimes possible to replace all or part of the pharmacophore with a biologically equivalent fragment called a bioisostere. Since functional groups are responsible not only for drug–receptor interac- tions but also for metabolic properties, the metabophore and the pharmacophore tend to be inextricably overlapped. Nevertheless, from the viewpoint of drug design, it is some- times possible to manipulate the structure of either the pharmacophore or the molecu- lar baggage portions of the drug molecule to achieve a metabophore that overcomes problems with liver-mediated first pass effects or that either hastens or delays renal excretion (see figure 1. The most important fragment is the pharmacophore, with the functional groups of the pharmacophore being displayed on a molecular framework composed of metabolically inert and conformationally constrained structural units. These structural units may be an alkyl chain, an aromatic ring, or a section of peptide chain backbone. When designing or constructing a drug molecule, one can thus pursue a fragment-by- fragment building block approach. In conceptualizing this approach, one sees that certain molecular fragments, although structurally distinct from each other, may behave identi- cally within the biological milieu of the receptor microenvironment. These structurally distinct yet biofunctionally equivalent molecular fragments are referred to as bioisosteres. In designing analogs of this drug, it would be possible to replace the sulphonate with a bioisosteri- cally equivalent carboxylate group. The carboxylate group would be able to interact electrostatically with the ammonium functional group in a fashion analogous to the sulphonate moiety. This bioisosteric substitution would bring additional advantages such as a prolonged half-life for the drug molecule since the carboxylate is less polar than the sulphonate and is thus less susceptible to rapid renal excretion. For example, H- may be replaced by F-; a carbonyl group (C=O) may be replaced by a thiocarbonyl group (C=S); a sulphonate may be replaced by a phosphonate. Classical bioisosteres are functional groups that possess similar valence electron configurations. Non-classical bioisosteres are functional groups with dissimilar valence electron configurations; for instance, a tetrazole moiety may be used to replace a car- boxylate since many biological systems are unable to differentiate between these two very structurally distinctive functional groups (see figure 1. A systematic explo- ration of bioisosteres when constructing drug molecules as collections of molecular fragments enables a rigorous structural consideration of varying pharmacophores and their properties during the pharmaceutical, pharmacokinetic, and pharmacodynamic phases of drug action. These are biologically equivalent molecular fragments that can be used to replace portions of a drug molecule. These properties dictate the therapeutic, toxic, and metabolic characteristics of the over- all drug molecule. These properties also completely control the ability of the drug to withstand the arduous journey from the point of administration to the receptor site buried deep within the body. These physical properties of drug molecules may be categorized into the following major groupings: 1.

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