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Ebook Handbook of experimental pharmacology: Part 2

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Ebook Handbook of experimental pharmacology: Part 2

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2e a vast array of biological processes and play a fundamental role in mammalian physiology. As a result, considerable diurnal variation in the pharmac

okinetics, efficacy, and side effect profiles of many therapeutics has been described. This variation has subsequently been lied to diurnal rhythms in Ebook Handbook of experimental pharmacology: Part 2

absorption, distribution, metabolism, and excretion, as well as in pharmacodynamic variables, such as target expression. More recently, the molecular

Ebook Handbook of experimental pharmacology: Part 2

basis of circadian rhythmicity has been elucidated with the identification of clock genes, which oscillate in a circadian manner in most cells and ti

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2n the regulation of pharmacologic parameters, as well as the reciprocal impact of drugs on circadian clock function. This chapter will review the role

of circadian clocks in the pharmacokinetics and pharmacodynamics of drug response and provide several examples of the complex regulation of pharmacol Ebook Handbook of experimental pharmacology: Part 2

ogic systems by components of the molecular circadian clock.Keywords Circadian clock • Pharmacology • Pharmacokinetics • Pharmacodynamics • CLOCK • Bm

Ebook Handbook of experimental pharmacology: Part 2

allE.s. MustekDepartment of Neurology. Washington University School of Medicine. 7401 Byron PI.Saint Louis. MO 63105, USAG.A. FitzGerald (23)Departmen

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2dicine. 3400 Civic Center Blvd. Bldg 421, Philadelphia. PA 19104-5158. USAe-mail: garret@upenn.eduA. Kramer and M. Merrow (eds.). Circadian Clocks, Ha

ndbook of Experimental243on IVM IO inm/mo 0 A4O ocncn n in244E.s. Musiek and G.A. FitzGerald1IntroductionThe maintenance of homeostasis is essential f Ebook Handbook of experimental pharmacology: Part 2

or all biological systems and requires rapid adaptation to the surrounding environment. The evolution of circadian rhythms in mammals exemplifies this

Ebook Handbook of experimental pharmacology: Part 2

, as organisms have developed mechanisms for physiologic modulation to match the varying conditions dictated by a 24-h light- dark cycle. An immense b

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2machinery responsible for generating and maintaining circadian rhythms has been described, and it has become clear that these cell autonomous molecula

r clocks ultimately control organismal circadian rhythmicity, from endocrine function to complex behavior. Because circadian rhythms are so fundamenta Ebook Handbook of experimental pharmacology: Part 2

l to mammalian physiology, it stands to reason that circadian physiologic variation would have significant implications for pharmacology. Indeed, many

Ebook Handbook of experimental pharmacology: Part 2

studies have demonstrated that circadian regulation plays an important role in both the pharmacokinetics and pharmacodynamics of many drugs. Cellular

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2ar circadian clock. As a result, circadian regulation can have substantial impact on the efficacy and side effect profile of therapeutics and should t

hus be considered when developing drug dosing regimens, measuring drug levels, and evaluating drug efficacy. The resultant field of chronopharmacology Ebook Handbook of experimental pharmacology: Part 2

is dedicated to understanding the importance of time of day in pharmacology and to optimizing drug delivery and design based on circadian regulation

Ebook Handbook of experimental pharmacology: Part 2

of pharmacologic parameters. In this chapter, we will briefly describe the molecular basis of the circadian clock, we will review studies demonstratin

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2ock influences pharmacologic targets. The goal of this chapter is to provide a framework within which to consider circadian influences on future inves

tigations in pharmacology.2Molecular Anatomy of the Mammalian Circadian SystemThe generation and maintenance of circadian rhythms in mammals depends b Ebook Handbook of experimental pharmacology: Part 2

oth on core molecular machinery' and on a complex anatomical organization. As a result, circadian rhylhmicity requires functional cell autonomous osci

Ebook Handbook of experimental pharmacology: Part 2

llation (Buhr and Takahashi 2013), neuroanatomical circuitry and neurotransmission (Slat Ct al. 2013). and paracrine and endocrine signaling systems (

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2cation with the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is entrained to light by an input from the retina

(Reppcrt and Weaver 2(X)2). The SCNMolecular Clocks in Pharmacology245synchronizes peripheral clocks in various organs to light input via regulation Ebook Handbook of experimental pharmacology: Part 2

of diverse systems including the autonomic nervous system, the pineal gland, and the hypothalamic-pituitary axis. Nevertheless, isolated peripheral ti

Ebook Handbook of experimental pharmacology: Part 2

ssues and even cultured cells maintain circadian rhylhmicily in the absence of input from the SCN (Baggs Ct al. 2009). The core molecular clock compon

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2lhydrocarbon receptor nuclear translocator single-minded protein (bIILII/PAS) transcription factors that helerodimerize and bind to E-box motifs in a

number of genes, driving transcription (Reppcrt and Weaver 2(X)2). Another bin.II/PAS transcription factor, NPAS2, which is highly expressed in the fo Ebook Handbook of experimental pharmacology: Part 2

rebrain, can alternatively heterodimerize with Bmall to facilitate transcription (Reick et al. 2001; Zhou et al. 1997). Bmall/ CLOCK drives transcript

Ebook Handbook of experimental pharmacology: Part 2

ion of several distinct negative feedback (“negativelimb”) components, including two cryptochrome (Cry 1,2) genes and three Period genes (Pcrl-3). Per

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2ed by two other Bmall/CLOCK targets, RORa (retinoid-related orphan receptor alpha) and REV-ERB«. RORa binds to specific elements and enhances Bmall tr

anscription (Akashi and Takumi 2005; Sato Ct al. 2004). REV-ERBa, another orphan nuclear receptor involved in glucose sensing and metabolism, competes Ebook Handbook of experimental pharmacology: Part 2

with RORa for DNA binding and suppresses Bmall transcription (Preitner el al. 2002). The core clock machinery (referred to herein as the circadian cl

Ebook Handbook of experimental pharmacology: Part 2

ock) is found in most tissues and has been estimated to mediate the circadian transcription of roughly 10-20 % of active genes (Ptitsyn Ct al. 2006).R

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2ircadian protein CLOCK has intrinsic histone acetyltransferase activity and can thus participate in epigenetic regulation of chromatin structure and a

cetylation of other proteins, including molecular clock components (Doi et al. 2006; Etchegaray el al. 2003; Sahar and Sassone-Corsi 2013). Indeed, po Ebook Handbook of experimental pharmacology: Part 2

sttranslational modifications of molecular clock proteins, including phosphorylation. SUMOylation. and acetylation, are critical for tuning of molecul

Ebook Handbook of experimental pharmacology: Part 2

ar clock function (Cardone Ct al. 2005; Gallego and Virshup 2007; Lee el al. 2001). Clock function is modified via input from diverse signaling protei

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2e metabolic sensor AMP kinase (Lamia el al. 2009), and the DNA repair protein Poly-ADP ribose polymerase (Asher Ct al. 2010). Molecular clock function

is also sensitive to the redox status of the cell (Rutter el al. 2001) and in Him regulates intracellular NAD+ levcls through regulation of the enzym Ebook Handbook of experimental pharmacology: Part 2

e nicotinamide phosphoribosyltransfcrasc (NAMPT) (Nakahata Ct al. 2(X)9; Ramsey et al. 2009). Thus, the molecular clock is sensitive to a wide array o

Ebook Handbook of experimental pharmacology: Part 2

f physiologic (and pharmacologic) cues.246E.s. Musiek and G.A. FitzGerald3Circadian Regulation of PharmacokineticsCircadian systems have been shown to

Part IIIChronopharmacology and ChronotherapyMolecular Clocks in PharmacologyErik s. Musiek and Garret A. FitzGeraldAbstract Circadian rhythms regulate

Ebook Handbook of experimental pharmacology: Part 2. Thus, time of day of drug administration, as well as the synchronization of the peripheral molecular clocks in several key organs (including the gut

. liver, and drug target tissue), can have substantial effect on drug levels and bioavailability.3.1 AbsorptionThe absorption of orally administered d Ebook Handbook of experimental pharmacology: Part 2

rugs depends on several factors including physiologic parameters of the GI tract (blood flow. pH. gastric emptying) and expression and function of spe

Ebook Handbook of experimental pharmacology: Part 2

cific uptake and efflux pumps on epithelial cell surfaces. Gastric pH plays an important role in the absorption of drugs, as lipophilic molecules are

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