Advances in pharmacology最新文献

Atypical kinetics are observed in metabolic reactions catalyzed by cytochrome P450 enzymes (P450). Yet, this phenomenon is regarded as experimental artifacts in some instances despite increasing evidence challenging the assumptions of typical Michaelis-Menten kinetics. As P450 play a major role in the metabolism of a wide range of substrates including drugs and endogenous compounds, it becomes critical to consider the impact of atypical kinetics on the accuracy of estimated kinetic and inhibitory parameters which could affect extrapolation of pharmacological and toxicological implications. The first half of this book chapter will focus on atypical non-Michaelis-Menten kinetics (e.g. substrate inhibition, biphasic and sigmoidal kinetics) as well as proposed underlying mechanisms supported by recent insights in mechanistic enzymology. In particular, substrate inhibition kinetics in P450 as well as concurrent drug inhibition of P450 in the presence of substrate inhibition will be further discussed. Moreover, mounting evidence has revealed that despite the high degree of sequence homology between CYP3A isoforms (i.e. CYP3A4 and CYP3A5), they have the propensities to exhibit vastly different susceptibilities and potencies of mechanism-based inactivation (MBI) with a common drug inhibitor. These experimental observations pertaining to the presence of these atypical isoform- and probe substrate-specific complexities in CYP3A isoforms by several clinically-relevant drugs will therefore be expounded and elaborated upon in the second half of this book chapter.

Cannabis legalization continues to progress in many US states and other countries. Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is the major psychoactive constituent in cannabis underlying both its abuse potential and the majority of therapeutic applications. However, the neural mechanisms underlying cannabis action are not fully understood. In this chapter, we first review recent progress in cannabinoid receptor research, and then examine the acute CNS effects of Δ⁹-THC or other cannabinoids (WIN55212-2) with a focus on their receptor mechanisms. In experimental animals, Δ⁹-THC or WIN55212-2 produces classical pharmacological effects (analgesia, catalepsy, hypothermia, hypolocomotion), biphasic changes in affect (reward vs. aversion, anxiety vs. anxiety relief), and cognitive deficits (spatial learning and memory, short-term memory). Accumulating evidence indicates that activation of CB₁Rs underlies the majority of Δ⁹-THC or WIN55121-2's pharmacological and behavioral effects. Unexpectedly, glutamatergic CB₁Rs preferentially underlie cannabis action relative to GABAergic CB₁Rs. Functional roles for CB₁Rs expressed on astrocytes and mitochondria have also been uncovered. In addition, Δ⁹-THC or WIN55212-2 is an agonist at CB₂R, GPR55 and PPARγ receptors and recent studies implicate these receptors in a number of their CNS effects. Other receptors (such as serotonin, opioid, and adenosine receptors) also modulate Δ⁹-THC's actions and their contributions are detailed. This chapter describes the neural mechanisms underlying cannabis action, which may lead to new discoveries in cannabis-based medication development for the treatment of cannabis use disorder and other human diseases.

Behavioral pharmacology has made vital contributions to the concepts and methods used in tobacco and other drug use research, and is largely responsible for the now generally accepted notion that nicotine is the primary component in tobacco that engenders and maintains tobacco use. One of the most important contributions of behavioral pharmacology to the science of drug use is the notion that drugs can act as environmental stimuli that control behavior in many of the same ways as other stimuli (e.g., visual, gustatory, olfactory). The purpose of this chapter is to provide an overview of research that illustrates the respondent and operant stimulus functions of nicotine, using a contemporary taxonomy of stimulus functions as a general framework. Each function is formally defined and examples from research on the behavioral pharmacology of nicotine are presented. Some of the factors that modulate each function are also discussed. The role of nicotine's stimulus functions in operant and respondent theories of tobacco use is examined and some suggestions for future research are presented. The chapter illustrates how a taxonomy of stimulus functions can guide conceptions of tobacco use and direct research and theory accordingly.

Cynomolgus macaques (Macaca fascicularis, an Old World monkey) are widely used in drug development because of their genetic and physiological similarities to humans, and this trend has continued with the use of common marmosets (Callithrix jacchus, a New World monkey). Information on the major drug-metabolizing cytochrome P450 (CYP, P450) enzymes of these primate species indicates that multiple forms of their P450 enzymes have generally similar substrate selectivities to those of human P450 enzymes; however, some differences in isoform, activity, and substrate specificity account for limited species differences in drug oxidative metabolism. This review provides information on the P450 enzymes of cynomolgus macaques and marmosets, including cDNA, tissue expression, substrate specificity, and genetic variants, along with age differences and induction. Typical examples of important P450s to be considered in drug metabolism studies include cynomolgus CYP2C19, which is expressed abundantly in liver and metabolizes numerous drugs. Moreover, genetic variants of cynomolgus CYP2C19 affect the individual pharmacokinetic data of drugs such as R-warfarin. These findings provide a foundation for understanding each P450 enzyme and the individual pharmacokinetic and toxicological results in cynomolgus macaques and marmosets as preclinical models. In addition, the effects of induction on some drug clearances mediated by P450 enzymes are also described. In summary, this review describes genetic and acquired individual differences in cynomolgus and marmoset P450 enzymes involved in drug oxidation that may be associated with pharmacological and/or toxicological effects.

With the availability of detailed genomic data on all 57 human cytochrome P450 genes, it is clear that there is substantial variability in gene product activity with functionally significant polymorphisms reported across almost all isoforms. This article is concerned mainly with 13 P450 isoforms of particular relevance to xenobiotic metabolism. After brief review of the extent of polymorphism in each, the relevance of selected P450 isoforms to both adverse drug reaction and disease susceptibility is considered in detail. Bleeding due to warfarin and other coumarin anticoagulants is considered as an example of a type A reaction with idiosyncratic adverse drug reactions affecting the liver and skin as type B. It is clear that CYP2C9 variants contribute significantly to warfarin dose requirement and also risk of bleeding, with a minor contribution from CYP4F2. In the case of idiosyncratic adverse drug reactions, CYP2B6 variants appear relevant to both liver and skin reactions to several drugs with CYP2C9 variants also relevant to phenytoin-related skin rash. The relevance of P450 genotype to disease susceptibility is also considered but detailed genetic studies now suggest that CYP2A6 is the only P450 relevant to risk of lung cancer with alleles associated with low or absent activity clearly protective against disease. Other cytochrome P450 genotypes are generally not predictors for risk of cancer or other complex disease development.