Elucidating Rifampin's Inducing and Inhibiting Effects on Glyburide Pharmacokinetics and Blood Glucose in Healthy Volunteers: Unmasking the Differential Effects of Enzyme Induction and Transporter Inhibition for a Drug and Its Primary Metabolite

Zheng, HX; Huang, Yong; Frassetto, LA; Benet, LZ

doi:10.1038/clpt.2008.186

Cited by 118 publications

(109 citation statements)

References 32 publications

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“…In contrast, repaglinide administered either 1 or 24 h after final rifampin administration displayed more than 3-fold difference in the extent of DDI (1.5-versus 4.9-fold change in repaglinide AUC, respectively) despite the same dose of victim drug (4 mg) and similar rifampin dose and duration (Ͼ5 days, 600 mg/day) (Bidstrup et al, 2004). The complexity of repaglinide disposition (hepatic uptake via OATP1B1 and differential contribution of CYP3A4 and CYP2C8 metabolism) in conjunction with multiple interaction mechanisms associated with rifampin (Zheng et al, 2009) may explain this dose-staggering effect; the most pronounced induction was observed when repaglinide was administered 24 h after rifampin.…”

Section: Downloaded Frommentioning

confidence: 99%

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

Templeton¹,

Houston²,

Galetin³

2011

Drug Metab Dispos

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ABSTRACT:Rifampin is a potent inducer of CYP3A4 in vitro and precipitates numerous drug-drug interactions (DDIs) when coadministered with CYP3A4 substrates. In the current study, we have critically assessed reported rifampin in vitro CYP3A4 induction data in Fa2N-4, HepaRG, and cryopreserved or primary human hepatocytes, using either CYP3A4 mRNA or probe substrate metabolism as induction endpoints. An in vivo data base of intravenously administered victim drugs (assuming hepatic induction only) was collated (n ‫؍‬ 18) to assess the predictive utility of these in vitro systems and to optimize rifampin in vivo E max . In addition, the effect of substrate hepatic extraction ratio on prediction accuracy was investigated using prediction boundaries proposed recently (Drug Metab Dispos 39:170-173). Incorporation of hepatic extraction ratio in the prediction model resulted in accurate prediction of 89% of intravenous induction DDIs (n ‫؍‬ 18), regardless of the in vitro system or induction endpoint (mRNA or CYP3A4 activity). Effects of in vitro parameters from different cellular systems, and optimized in vivo E max , on the prediction of 21 oral DDIs were assessed. Use of mRNA data resulted in pronounced overprediction across all systems, with 86 to 100% of DDIs outside the acceptable prediction limits; in contrast, CYP3A4 activity predicted up to 62% of the oral DDIs within limits. Although prediction accuracy of oral DDIs was improved when using intravenous optimized rifampin E max , >35% of DDIs were incorrectly assigned, suggesting potential differential E max between intestine and liver. Implications of the findings and recommendations for prediction of rifampin DDIs are discussed.

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Section: Downloaded Frommentioning

confidence: 99%

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

Templeton¹,

Houston²,

Galetin³

2011

Drug Metab Dispos

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“…For example, the class 2 drug felodipine has been shown not to be affected by the intestinal or hepatic efflux transporters (20). Recently, our laboratory has shown the importance in humans of hepatic uptake transporters for the drugs atorvastatin and glyburide (21,22). These interactions were predicted based on cellular, isolated organ, and animal studies (22)(23)(24).…”

Section: Cautionmentioning

confidence: 99%

BDDCS Applied to Over 900 Drugs

Benet

Broccatelli

Oprea

2011

AAPS J

563

529

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Abstract. Here, we compile the Biopharmaceutics Drug Disposition Classification System (BDDCS) classification for 927 drugs, which include 30 active metabolites. Of the 897 parent drugs, 78.8% (707) are administered orally. Where the lowest measured solubility is found, this value is reported for 72.7% (513) of these orally administered drugs and a dose number is recorded. The measured values are reported for percent excreted unchanged in urine, LogP, and LogD 7.4 when available. For all 927 compounds, the in silico parameters for predicted Log solubility in water, calculated LogP, polar surface area, and the number of hydrogen bond acceptors and hydrogen bond donors for the active moiety are also provided, thereby allowing comparison analyses for both in silico and experimentally measured values. We discuss the potential use of BDDCS to estimate the disposition characteristics of novel chemicals (new molecular entities) in the early stages of drug discovery and development. Transporter effects in the intestine and the liver are not clinically relevant for BDDCS class 1 drugs, but potentially can have a high impact for class 2 (efflux in the gut, and efflux and uptake in the liver) and class 3 (uptake and efflux in both gut and liver) drugs. A combination of high dose and low solubility is likely to cause BDDCS class 4 to be underpopulated in terms of approved drugs (N=53 compared with over 200 each in classes 1-3). The influence of several measured and in silico parameters in the process of BDDCS category assignment is discussed in detail.KEY WORDS: BDDCS; biowaiver; dose number; extent of metabolism; permeability rate.In 2005, Wu and Benet (1) introduced the Biopharmaceutics Drug Disposition Classification System (BDDCS). Wu and Benet recognized that there was a very strong correlation between the intestinal permeability rate and the extent of metabolism. For example, Benet et al. (2) noted that for the 29 drugs and endogenous substances for which human jejunal permeability rate measurements were available, there was an excellent correlation between these permeability rate measurements and the extent of drug metabolism in humans. Fourteen of the 16 drugs exhibiting human intestinal permeability rates greater than metoprolol were extensively metabolized, while 11 of 12 drugs showing permeability rates less than metoprolol were poorly metabolized. Two drugs showing disparity between the permeability rate and metabolism, cephalexin and losartan, exhibit permeability rates that differ by no more than 16% from metoprolol (2). Since the coefficients of variation for the human permeability parameters range from 29% to 130%, these borderline compounds may in fact also have followed the correlation. The correlation between the extent of metabolism and human intestinal jejunal permeability was markedly better than that observed for intestinal jejunal permeability and partition coefficient by Takagi et al. (3), who noted that Log P measured and calculated correctly predict high versus low permeability only about two thir...

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“…However, there were also studies indicating that M1 and M2b retain 75% and 50%, respectively, of the hypoglycemic activity of glyburide in humans . The systemic exposure of M1 is only 2 -4% of that of glyburide (Zheng et al, 2009). The pharmacological activity of other glyburide metabolites is currently not known.…”

Section: Glyburide and Its Clinical Pharmacokineticsmentioning

confidence: 99%