Effects of Repeated Clarithromycin Administration on the Pharmacokinetic Properties of Pindolol in Rats.

Komori, Takafumi; Shimoishi, Kazuki; Harashima, Hideyoshi; Otagiri, Masaki

doi:10.1248/bpb.21.1376

Cited by 4 publications

(2 citation statements)

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“…Therefore, because the degree of ONO-2160 hydrolysis in plasma may increase with increasing F1*S expression in such patients, changes in the expression level of AGP and in the ratio of variants are important pharmacokinetic considerations when discussing the metabolism of drugs that are mainly hydrolyzed by AGP, such as ONO-2160. Repeated administration of clarithromycin also increases the plasma AGP concentration; therefore, the degree of AGP hydrolysis may increase because of an increase in the AGP concentration not only during pathological conditions but also when such drugs are used in combination.…”

Section: Discussionmentioning

confidence: 99%

Hydrolase Activity of the Genetic Variants of Human Alpha-1-Acid Glycoprotein

et al. 2022

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In human plasma, the main agent of hydrolysis of the ester-type prodrug of levodopa, designated ONO-2160, is alpha-1-acid glycoprotein (AGP), which is a mixture of the F1*S and A variants at molar ratios of 3:1 to 2:1. In this study, the mechanism of AGP esterase-like activity was investigated by evaluating the contribution of the F1*S and A variants to ONO-2160 hydrolysis and identifying the AGP hydrolase active site. We found that although both variants hydrolyzed ONO-2160, their hydrolase activities were different. The intrinsic plasma clearance of the F1*S variant (0.441 mL/h/mg protein) was approximately 30 times higher than that of the A variant (0.0148 mL/h/mg protein), indicating that the F1*S variant contributed the most to AGP esterase-like activity. To identify the hydrolase active site of AGP, we performed inhibition studies of ONO-2160 hydrolysis using 12 AGP-binding drugs with various ligand-binding constants and binding selectivities to the two AGP variants. Inhibition of activity was positively correlated with the constant of ligand binding to the F1*S variant. In addition, compounds with high affinity to the F1*S variant inhibited ONO-2160 hydrolysis the most. Together, our data indicate that ONO-2160 is predominantly hydrolyzed by the F1*S variant at its ligand-binding site.

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Section: Discussionmentioning

confidence: 99%

Hydrolase Activity of the Genetic Variants of Human Alpha-1-Acid Glycoprotein

et al. 2022

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“…Because the proportions of protein-bound pindolol in plasma or serum have been reported to be 52% in rats [50] and 57% in humans [51], and because no metabolites of this drug active at 5-HT 1A receptors have been identified, we assumed that there were no species differences in the relationships between plasma pindolol concentration and 5-HT 1A receptor occupancy. In clinical assays, data on the plasma concentration of pindolol to induce full occupancy of receptors are lacking due to concerns about side effects at such high doses, and this may hamper accurate determination of EC 50 in humans, conceivably resulting in a slight difference in EC 50 values between non-clinical and clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Presynaptic Selectivity of a Ligand for Serotonin 1A Receptors Revealed by In Vivo PET Assays of Rat Brain

Saijo

Maeda²,

Okauchi³

et al. 2012

PLoS ONE

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A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT1A) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT1A receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT1A receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT1A receptors. In addition, [35S]guanosine 5′-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT1A receptors. This finding has lent support to reports that diverse partial agonists for 5-HT1A receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

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Study on Binding of Drug to Serum Protein

Otagiri

2009

YAKUGAKU ZASSHI

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After being distributed in the circulating blood, drugs bind to serum proteins varying degrees. In general, such binding is reversible, and a dynamic equilibrium exists between the bound and unbound molecular species. It is believed that unless there is a speciˆc transport system (e.g. receptor-mediated endocytosis, protein-mediated transport), only unbound drugs are able to penetrate through biomembranes, are distributed to tissues, and undergo metabolism and glomerularˆltration. It is also believed that only unbound molecules present in target tissues can exert their pharmacological eŠects, and that the concentration of unbound molecules in tissues is in proportion to the drug serum concentration. Therefore, drug-serum protein binding is critically involved in the manifestation of the pharmacological eŠects of a drug as well as its pharmacokinetics. Among serum proteins, human serum albumin (HSA) and a 1 -acid glycoprotein (AGP) play important roles in protein binding for many drugs, which is of key importance to drug distribution in the body. In addition, they are widely used in clinical settings as blood preparations and drug delivery system carriers. It is thus of great importance from the viewpoint of pharmaceutical science to clarify the structure, function, and pharmaceutical properties of HSA and AGP. Accordingly, since starting my laboratory, the focus of my research has involved molecular pharmaceutical studies on the interactions of drugs and HSA and AGP for the purpose of applying theseˆndings to clinicalˆelds, such as drug treatment, diagnosis and drug discovery. In this review, the molecular properties of HSA and AGP will be brie‰y outlined. The static and dynamic topology of drug binding sites on these proteins, investigated by various spectroscopic techniques, X-ray crystallography, quantitative structure-activity relationships, molecular modeling, photo a‹nity labeling, site-directed mutagenesis etc., changes in the serum protein binding of drugs in pathological conditions, such as liver and kidney failure and various in‰ammation diseases and factors contributing to the changes will then be summarized. Finally, cases in which protein binding displacement can be applied to medicalˆelds will also be introduced.

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Effects of Repeated Clarithromycin Administration on the Pharmacokinetic Properties of Pindolol in Rats.

Cited by 4 publications

References 0 publications

Hydrolase Activity of the Genetic Variants of Human Alpha-1-Acid Glycoprotein

Hydrolase Activity of the Genetic Variants of Human Alpha-1-Acid Glycoprotein

Presynaptic Selectivity of a Ligand for Serotonin 1A Receptors Revealed by In Vivo PET Assays of Rat Brain

Study on Binding of Drug to Serum Protein

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