Paper 5 Answers
James Day, Amy Thomson, Tamsin McAllister, Nawal Bahal in Get Through, 2014
Biguanides such as metformin act by increasing peripheral insulin sensitivity and therefore increase glucose uptake into cells, reducing plasma glucose concentration. In addition, they prevent production of glucose from hepatic and renal gluconeogenesis. Thiazolidenediones (e.g. rosiglitazone, pioglitazone) also increase peripheral insulin sensitivity by gene regulation. 15A: True15B: True15C: True15D: False15E: TrueA prodrug is a drug that has no inherent activity before metabolism but following metabolism in the body is converted into an active compound. This can be used to overcome problems with administration of the active drug, for example, a more lipid soluble prodrug with better absorption and diffusion across cell membranes can be metabolized to a more water-soluble compound once at the target site. It can also be used to bypass metabolism of the active drug.
For example, levodopa (L-DOPA) is the amino acid precursor of dopamine.
It is used in the treatment of Parkinson’s disease.
Dopamine is unable to cross the blood–brain barrier but L-DOPA can, where it is converted into dopamine to have its action.
Examples of prodrugs are:
Diamorphine: metabolized to 6-monoacylmorphine
Enalapril: metabolized to enaloprilat
Parecoxib: metabolized to valdecoxib
Terlipressin: metabolized to vasopressin
Biopharmaceutics
Shein-Chung Chow in Encyclopedia of Biopharmaceutical Statistics, 2018
While optimizing the stability and the biopharmaceutical properties of new drug candidates toward the formulation of consistent performance, the choice of free acid or base or salt form is important. Usually, the salt form of the weak base or acid drug made with the strong counterion, such as chloride or sodium, respectively, is more soluble and more rapidly dissolved than is the parent compound. Examples of basic drugs for which this prevails are the hydrochloride salts of epinephrine and quinidine; whereas for acids, such as barbitals, the sodium salt is better dissolved. However, examples of free bases that are more soluble than the hydrochloride salt forms at gastric pH are chlortetracycline and methacycline, although the related tetracycline is marketed mainly as the hydrochloride salt. An interesting example is naproxen, which is formulated for chronic pain use as the acid, whereas the sodium salt (which is more rapidly dissolved) is prescribed for fast-acting analgesia. In the preformulation assessment of inhalant dosage forms, the salt form is important. Many of the drugs formulated in these devices are weak bases prepared as salts, and the pH of solution with strong counterions such as chloride or sulfate could be problematic. Solutions with pH below 2 can cause bronchoconstriction, and thus weaker acid salts may have to be chosen. Prodrugs are chemical modifications of drugs that are rapidly metabolized to active drug in the body, often at the intestinal villi. They are usually designed to be more lipid-soluble and thus provide better absorption. Ampicillin esters, bacampicillin and pivampicillin, were developed to improve the bioavailability of the active parent, ampicillin. Enalapril is the weakly active ethyl ester, converted to the diacid enalaprilat, which is a powerful angiotensin converting enzyme inhibitor. Valacyclovir is the l-valine ester of the active antiviral, acyclovir, which itself is poorly absorbed, and the de-esterification yields much higher serum concentrations of acyclovir by the oral route.
Special Problems in Structures of Drugs
Joseph Chamberlain in The Analysis of Drugs in Biological Fluids, 2018
Prodrugs are chemical structures which are not pharmacologically active, but in the body are converted to an active molecule. In general, the prodrug has chemical characteristics, such as stability, lipophilicity, state of ionisation, that increase its chances of reaching its site of action, or which protect intervening biological structures from the effect of the active drug (taste, toxicity). Ideally, the prodrug should be converted to the active form at the site of action, particularly if the active form would be toxic at other sites. This is particularly true of anticancer drugs which are usually directed at killing cells. Table 3.6 shows a number of prodrugs and their active degradation products. The use of prodrugs does not offer a particular problem to the analyst in chemical terms. However, the pharmacokineticist needs to distinguish between the needs of measuring the parent compound or the active compound, depending on the object of the study. For example, if the project is to investigate the absorption of the administered drug (i.e., to investigate formulations), then it is sensible to measure the appearance of unchanged compound in the blood and to apply classical bioavailability theory. If, on the other hand, the investigator wants to compare potential utility of the drug, then the levels of the active product, preferably at the site of action, are more relevant. A particular form of prodrug is found in the conjugation of the drug molecule to polymers as described for the polypeptide R-(a-acetyl)eglin c conjugated to poly(oxyethylene) to give a macromolecule of molecular weight >20,000.
Acetal-linked polymeric prodrug micelles based on aliphatic polycarbonates for paclitaxel delivery: preparation, characterization,
Published in Journal of Biomaterials Science, Polymer Edition, 2020
Shiya Zhou, Shuwen Fu, Hanle Wang, Yanhao Deng, Xing Zhou, Wei Sun, Yinglei Zhai
Acidic tumor microenvironment has been extensively explored to design pH-responsive paclitaxel prodrug micelles for cancer therapy. The object of this study is to investigate the pH-responsive drug release behavior and the anti-proliferation capacity of acetal-linked paclitaxel polymeric prodrug micelles. The prodrug was synthesized and evaluated for paclitaxel content. The prodrug micelles were fabricated and characterized for morphology, size, in vitro pH-responsive paclitaxel release, cellular uptake, and anti-proliferation. Paclitaxel content was 33 wt%. The prodrug micelles exhibited spherical structure with the hydrodynamic diameter of 154 nm. Besides, the in vitro paclitaxel release behavior was verified to be pH-responsive, and 77%, 38%, and 17% of parent free paclitaxel was released from the nano-sized prodrug micelles in 13 h at pH 5.5, 6.5, and 7.4, respectively. The cellular uptake assessment demonstrated the time-dependent internalization of prodrug micelles. Meanwhile, CCK-8 analysis showed that prodrug micelles possessed the potent anti-proliferation effects. Prodrug micelles based on aliphatic polycarbonates present a promising platform for cancer chemotherapy due to the pH-responsive characteristics of acetal bond, potent anti-proliferation effects, and outstanding cytocompatibility of aliphatic polycarbonates.
What should be considered on design of a colon-specific prodrug?
Published in Expert Opinion on Drug Delivery, 2010
Importance of the field: Generally, a prodrug, a pharmacologically inactive derivative of an active drug, is designed to modulate pharmacokinetic properties of the parent drug. Targeted distribution of an orally administered drug at the large intestine confers therapeutic advantages on treatment of colonic diseases, peptide and protein therapy and chronotherapy. Areas covered in this review: To achieve such distribution control in the gastrointestinal tract, the adoption of the prodrug concept gives birth to a colon-specific prodrug. The requirement for a prodrug to be colon-specific is described along with the necessary and sufficient conditions of drugs for conversion to a colon-specific prodrug. The known and previously unnoticed factors that negatively influence therapeutic activity and reproducibility of a colon-specific prodrug are presented with suggestions to minimize the negative influence. What the reader will gain: This review provides tactics to satisfy the requirements for being colon-specific and the potential strategies to circumvent obstacles in developing an efficient colon-specific prodrug. Take home message: On design of a colon-specific prodrug, one should take into consideration not only delivery of a drug to the target site, but also the therapeutic effectiveness there.
An improved synthesis of lysosomal activated mustard prodrug for tumor-specific activation and its cytotoxic evaluation
Published in Drug Development and Industrial Pharmacy, 2012
Raghuramreddy Adidala, Harikrishna Devalapally, Chandrasekhar Srivari, Krishna Devarakonda R, Akkinepally Raghuram Rao
Cyclophosphamide, an alkylating agent widely used as anticancer agent, biotransformed in vivo to unstable phosphoramidic mustard and acrolein, where the latter metabolite has been found responsible for hemorrhagic cystitis and renal toxicity. Being one of the most popular strategies to avoid these deleterious effects, prodrug design has been attempted, which can, in addition, enable selective drug targeting. Our efforts to design, synthesize and evaluate the enzymatically activated prodrug phosphorodiamidic mustard as potential candidate for selective chemotherapy in antibody-directed enzyme prodrug therapy or prodrug monotherapy strategies are described. We propose an improved synthesis of prodrug 14, consisting of a galactose moiety, a spacer and a cytotoxic drug and its cytotoxicity has been investigated. The prodrug 14 has been found to be nontoxic (in vitro) which could be a valuable candidate for further development.
Related Knowledge Centers
- Chemotherapy
- Human Gastrointestinal Tract
- Pharmaceutical Drug