Drug Glucuronidation in Clinical Psychopharmacology

Liston, Heidi L.; Markowitz, John S.; DeVane, C. Lindsay

doi:10.1097/00004714-200110000-00008

Cited by 162 publications

(97 citation statements)

References 111 publications

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“…-After oral administration, the drug is rapidly absorbed. Only 27-50 % of the dose reaches the systemic circulation unchanged because of extensive first-pass metabolism (25)(26)(27)(28). It is 95 % bound to plasma proteins, primarily alpha-1-acid glycoprotein.…”

Section: Tdm Of Particular Atypical Antipsychotic Drugsmentioning

confidence: 99%

Therapeutic drug monitoring of atypical antipsychotic drugs

2014

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Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic epi sodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM) of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results.

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Section: Tdm Of Particular Atypical Antipsychotic Drugsmentioning

confidence: 99%

Therapeutic drug monitoring of atypical antipsychotic drugs

2014

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“…The in vivo significance of this phenomenon could be important but is presently unknown, since there are no published reports indicating a clinical interaction with bilirubin or glucuronidation of UGT1A1 substrates. UGT1A1 is the sole enzyme responsible for the glucuronidation of bilirubin and contributes to the glucuronidation of several drugs including estradiol, irinotecan, buprenorphine, and naltrexone (Liston et al, 2001). The mean peak plasma concentration of silybin after oral administration of a 700-mg dose of silymarin (containing approximately 254 mg of silybin) is 0.6 M. Silybin undergoes primarily biliary excretion, and concentrations in the bile approximating 150 M have been reported (Weyhenmeyer et al, 1992).…”

Section: Sridar Et Almentioning

confidence: 99%

Silybin Inactivates Cytochromes P450 3a4 and 2c9 and Inhibits Major Hepatic Glucuronosyltransferases

Sridar¹,

Goosen

Kent³

et al. 2004

Drug Metabolism and Disposition

174

154

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ABSTRACT:Silybin, a major constituent of the milk thistle, is used to treat several liver disorders. Silybin inactivated purified, recombinant cytochromes P450 (P450) 3A4 and 2C9 in a mechanism-based manner. The inactivations were time-, concentration-, and NADPHdependent. The inactivation of the 7-benzyloxy-4-(trifluoromethyl-)coumarin O-debenzylation activity (P450 3A4) was characterized by a K I of 32 M, a k inact of 0.06 min ؊1 , and a t 1/2 of 14 min.Testosterone metabolism to 6-␤-hydroxytestosterone (P450 3A4) was also inactivated with a K I of 166 M, a k inact of 0.08 min ؊1, and a t 1/2 of 9 min. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of purified human P450 2C9 was inactivated with a K I of 5 M, a k inact of 0.14 min ؊1, and a t 1/2 of 7 min. Parallel loss of heme was observed with both P450s. Activity of both P450 enzymes was not recovered after removal of silybin either by dialysis or by spin gel filtration. In addition, silybin inhibited the glucuronidation of 7-hydroxy-4-trifluoromethylcoumarin catalyzed by recombinant hepatic UDP-glucuronosyltransferases (UGTs) 1A1, 1A6, 1A9, 2B7, and 2B15, with IC 50 values of 1.4 M, 28 M, 20 M, 92 M, and 75 M, respectively. Silybin was a potent inhibitor of UGT1A1 and was 14-and 20-fold more selective for UGT1A1 than for UGT1A9 and UGT1A6, respectively. Thus, careful administration of silybin with drugs primarily cleared by P450s 3A4 or 2C9 is advised, since drug-drug interactions cannot be excluded. The clinical significance of in vitro UGT1A1 inhibition is unknown.

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“…Glucuronidation is a major pathway in the elimination of exogenous compounds (Evans and Relling, 1999;King et al, 2000;Tukey and Strassburg, 2000). This phase II metabolic reaction is catalyzed by UGT enzymes that transfer the glucuronosyl group from UDP-glucuronic acid to lipophilic compounds such as bile acids, steroid hormones, or environmental pollutants, thus facilitating their disposition and/or altering their therapeutic efficacy or toxic manifestation (Liston et al, 2001). Glucuronidation is primarily a detoxification pathway; however, metabolic activation is also possible [e.g., morphine 6-glucuronide is therapeutically more potent than morphine per se (Glare and Walsh, 1991)].…”

mentioning

confidence: 99%

Glucuronidation of the Oxidative Cytochrome P450-Mediated Phenolic Metabolites of the Endocrine Disruptor Pesticide: Methoxychlor by Human Hepatic Udp-Glucuronosyl Transferases

Hazai

Gagne²,

Kupfer³

2004

Drug Metabolism and Disposition

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ABSTRACT:Methoxychlor, a currently used pesticide, is a proestrogen exhibiting estrogenic activity in mammals in vivo. Methoxychlor undergoes oxidative metabolism by cytochromes P450, yielding 1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane (mono-OH-M) and 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane (bis-OH-M) as main metabolites. Since humans may be exposed to these estrogenic metabolites, which are potential substrates of UDP-glucuronosyltransferases (UGTs), their glucuronide conjugation was investigated with human liver preparations and individual UGTs. Incubation of both mono-OH-M and bis-OH-M with human liver microsomes formed monoglucuronides. The structures of the glucuronides were identified by liquid chromatography/tandem mass spectometry. Examination of cDNA-expressed recombinant human hepatic UGTs revealed that several catalyze glucuronidation of both compounds. Among the cDNA-expressed UGT1A enzymes, UGT1A9 seemed to be the main catalyst of formation of mono-OH-M-glucuronide, whereas UGT1A3 seemed to be the most active in bis-OH-M-glucuronide formation. Furthermore, the chiral selectivity of mono-OH-M glucuronidation was examined. The results of the incubation of single enantiomers generally agreed with the chiral analyses of mono-OH-M derived from the glucuronidase digestion of the glucuronides of the racemic mono-OH-M. There was a relatively slight but consistent enantioselective preference of individual UGT1A1, UGT1A3, UGT1A9, and UGT2B15 enzymes for glucuronidation of the S-over the R-mono-OH-M, whereas in human liver microsomes differences were observed among donors in generating the respective R/S-mono-OH-M ratio. Since it was previously shown that human liver microsomes demethylate methoxychlor mainly into S-mono-OH-M, the observation that UGT1A isoforms preferentially glucuronidate the S-mono-OH-M suggests a suitable mechanism for eliminating this major enantiomer. This enantiomeric preference, however, is not extended to all samples of human liver microsomes that we tested.

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Drug Glucuronidation in Clinical Psychopharmacology

Cited by 162 publications

References 111 publications

Therapeutic drug monitoring of atypical antipsychotic drugs

Therapeutic drug monitoring of atypical antipsychotic drugs

Silybin Inactivates Cytochromes P450 3a4 and 2c9 and Inhibits Major Hepatic Glucuronosyltransferases

Glucuronidation of the Oxidative Cytochrome P450-Mediated Phenolic Metabolites of the Endocrine Disruptor Pesticide: Methoxychlor by Human Hepatic Udp-Glucuronosyl Transferases

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