Potential role for P-glycoprotein in the nonproportional pharmacokinetics of UK-343,664 in man

Abel, Sylvie; Kc, Beaumont; Cl, Crespi; Eve,; L, Fox; Hyland, Ruth; Bc, Jones; Gj, Muirhead; Da, Smith; Rf, Venn; Dk, Walker

doi:10.1080/00498250110052779

Cited by 42 publications

(68 citation statements)

References 9 publications

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“…In contrast, the clinical dose-exposure relationship in humans shows marked nonproportionality in terms of both AUC and C max , with superproportional increases observed up to doses of 300 mg. Dose-normalized exposure is approximately 10-fold higher at a dose of 300 mg compared with a dose of 3 mg. Based on an estimated fluid volume of 500 ml (Dressman et al, 1998) in the small intestine, a dose of 3 mg of UK-427,857 would result in a concentration of about 12 M, which is below the P-glycoprotein apparent K m of 37 M and, hence, would not be expected to saturate P-glycoproteinmediated efflux. This superproportional dose-exposure relationship is similar to that previously observed for a number of compounds including the NK2 antagonist, UK-224,671 (Beaumont et al, 2000), the ␣-antagonist, UK-294,315 (Harrison et al, 2004), and the phosphodiesterase 5 inhibitor, UK-343,664 (Abel et al, 2001). All of these compounds have arisen out of drug discovery programs that have either targeted enzyme inhibitors with subtype selectivity or are nonaminergic 7-transmembrane spanner receptor antagonists.…”

Section: Discussionsupporting

confidence: 68%

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Species Differences in the Disposition of the Ccr5 Antagonist, Uk-427,857, a New Potential Treatment for Hiv

Walker

Abel²,

Comby³

et al. 2005

Drug Metab Dispos

142

107

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UK-427,857 (4, 4-difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cy-clohexanecarboxamide) is a novel CCR5 antagonist undergoing investigation for use in the treatment of human immunodeficiency virus (HIV) infection.Pharmacokinetic and metabolism studies have been performed in mouse, rat, dog, and human after single and multiple administration by oral and intravenous routes. The compound has physicochemical properties that are borderline for good pharmacokinetics, being moderately lipophilic (log D 7.4 2.1) and basic (pK a 7.3), possessing a number of H-bonding functionalities, and with a molecular weight of 514. The compound was incompletely absorbed in rat (ϳ20-30%) but well absorbed in dog (>70%). Based on in vitro studies in Caco-2 cells, UK-427,857 has relatively poor membrane permeability, and transcellular flux is enhanced in the presence of inhibitors of P-glycoprotein. Further evidence for the involvement of P-glycoprotein in restricting the oral absorption of UK-427,857 was obtained in P-glycoprotein null mice (mdr1a/mdr1b knockout). In these animals, AUC after oral administration was 3-fold higher than in control animals. In oral dose escalation studies in humans, the compound demonstrated nonlinear pharmacokinetics, with increased dosenormalized exposure with increased dose size, consistent with saturation of P-glycoprotein. The oral dose-exposure relationship of UK-427,857 in humans was not reflected in either rat or dog. In animal species and humans, UK-427,857 undergoes some metabolism, with parent compound the major component present in the systemic circulation and excreta. Elimination of radioactive dose was primarily via the feces. In rat, parent compound was secreted via bile and directly into the gastrointestinal tract. Metabolites were products of oxidative metabolism and showed a high degree of structural consistency across species.The chemokine receptor, CCR5, acts as the major coreceptor involved in viral entry into the cell in the case of primary HIV infection. Therefore, blocking the CCR5 receptor prevents viral entry into host cells and should thus decrease viral load in HIV-1 infected individuals. This theory is supported by genetic evidence which shows that individuals lacking a functional CCR5 gene are highly resistant to HIV-1 infection (Liu et al., 1996;Samson et al., 1996;Chantry, 2004). UK-427,857 (4, 4-difluoro-N-{(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}-cyclohexanecarboxamide) is a novel CCR5 receptor antagonist designed through a rational drug discovery program and is currently undergoing clinical evaluation (Bayes et al., 2003). UK-427,857 has a molecular weight of 514 and is a moderately lipophilic (log D 7.4 ϭ 2.1) and basic (pK a ϭ 7.3) molecule. The empirical formula is C 29 H 41 F 2 N 5 O and the structure is shown in Fig. 1.Pharmacokinetic studies with UK-427,857 were undertaken in rat and dog during the discovery program leading to...

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Section: Discussionsupporting

confidence: 68%

“…P-gp Binding Affinity. The apparent binding affinity of UK-427,857 for recombinant human P-glycoprotein expressed in insect cell membranes was determined as previously described (Abel et al, 2001). Apparent kinetic parameters K m and V max were obtained by Michaelis-Menten analysis of the data.…”

Section: Downloaded Frommentioning

confidence: 99%

Species Differences in the Disposition of the Ccr5 Antagonist, Uk-427,857, a New Potential Treatment for Hiv

Walker

Abel²,

Comby³

et al. 2005

Drug Metab Dispos

142

107

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“…These data also suggest that UK-294,315 does not undergo major gut wall metabolism since systemic exposure (AUC 0-T ) remains linear over the entire dose range, despite variability in absorption rate. Saturation of P-gp by a substrate for cytochrome P450-mediated gut wall metabolism can lead to nonlinear increases in the extent of absorption (e.g., UK-343,664;Abel et al, 2001). ␣-Adrenergic receptor antagonists as a class are generally administered using a gastrointestinal, modified release formulation to improve the safety and/or pharmacokinetic profile of the drugs (e.g., doxazosin, prazosin, alfuzosin) (Elliott et al, 1988;Cases, 2000;Van Kerrebroeck et al, 2002).…”

Section: Fig 5 Mean Pharmacokinetic Profiles After Oral Administratmentioning

confidence: 99%

“…Affinity of UK-294,315 for human P-glycoprotein (P-gp) was determined using a previously described method of measuring phosphate release from P-gp membranes (Abel et al, 2001). Apparent kinetic parameters K m and V max were determined using Grafit 3.0 and the MichaelisMenten equation (eq.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Saturation of intestinal transporter proteins (e.g., P-glycoprotein) has been implicated in the nonlinear oral absorption of several drugs, including talinolol, celiprolol, and UK-343,664 (Milne and Buckley, 1991;Wetterich et al, 1996;Abel et al, 2001). Preclinical studies demonstrated that UK-294,315 is a substrate for active transport proteins (e.g., P-glycoprotein), a property now recognized as potentially leading to nonlinear oral pharmacokinetics (Ayrton and Morgan, 2001).…”

mentioning

confidence: 99%

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NONLINEAR ORAL PHARMACOKINETICS OF THE Α-Antagonist 4-Amino-5-(4-Fluorophenyl)-6,7-Dimethoxy-2-[4-(Morpholinocarbonyl)-Perhydro-1,4-Diazepin-1-Yl]quinoline IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS

Harrison

Betts²,

Fenner³

et al. 2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:4-Amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline (UK-294,315) is an antagonist of the human ␣ 1 -adrenoceptor and exhibits nonlinear oral pharmacokinetics in humans. Superproportional increases in C max occur (220-fold, over a 1-to 50-mg dose range), area under the curve increases linearly, but time to maximum concentration decreases with dose, suggesting variation in rate but not extent of absorption. Oral absorption in humans is extensive, with only 14% of an orally administered (20 mg) radiolabeled dose excreted unchanged in the feces. In rats and dogs, UK-294,315 is partially eliminated as unchanged drug in feces (29 and 14% of an intravenous dose, respectively). Oral bioavailability is low in rats (11%) and high in dogs (71%), in keeping with systemic clearance. Fecal elimination of unchanged drug was 60% after oral administration to rats, indicating incomplete absorption in this species, whereas absorption in dogs is complete. UK-294,315 is a P-glycoprotein (P-gp) substrate (K m , 15 M) exhibiting polarized flux in Caco-2 cell monolayers, saturable across a concentration range of 5 to 200 M. Furthermore, the observations in vitro occurred at similar concentrations to those estimated in the gut lumen in clinical trials (dose range, 1-100 mg). It is considered that P-gp acts as a saturable absorption barrier to UK-294,315, slowing the rate of absorption at low doses, and is responsible for the observed nonlinearity in oral disposition in humans. Rat and dog pharmacokinetic studies offered limited insight into the process(es) driving nonlinear pharmacokinetics in humans. Our current understanding of the functional effects of P-gp in the human intestine, in combination with in vitro studies at clinically relevant concentrations, has helped rationalize the clinical data for UK-294,315.4-Amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline (UK-294,315 1 ) (Fig. 1) is a novel potent antagonist of the human ␣ 1 -adrenoceptor found in the prostate, cardiovascular system, and other tissues. ␣ 1 -Adrenoceptor antagonists are well precedented in the effective treatment of hypertension and benign prostatic hyperplasia [e.g., doxazosin (Fulton et al., 1995) and tamsulosin (Wilde and McTavish, 1996)].Following progression to clinical studies, UK-294,315 exhibited nonlinear behavior in the rate, but not extent, of absorption over the dose range studied (1-100 mg). Nonlinear pharmacokinetics pose a challenge to the successful development of a drug candidate, especially when this behavior occurs across the therapeutic dose range. Such behavior complicates drug therapy due to extensive variability in exposure, which may lead to variable efficacy and narrow therapeutic window over potential adverse events. Indeed, nonlinear oral pharmacokinetics, within the commonly used dose range, of the recreational drug "ecstasy" are thought to result in cases of ...

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Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

El‐Kattan

Hurst

Brodfuehrer

et al. 2011

Oral Bioavailability

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Potential role for P-glycoprotein in the nonproportional pharmacokinetics of UK-343,664 in man

Cited by 42 publications

References 9 publications

Species Differences in the Disposition of the Ccr5 Antagonist, Uk-427,857, a New Potential Treatment for Hiv

Species Differences in the Disposition of the Ccr5 Antagonist, Uk-427,857, a New Potential Treatment for Hiv

NONLINEAR ORAL PHARMACOKINETICS OF THE Α-Antagonist 4-Amino-5-(4-Fluorophenyl)-6,7-Dimethoxy-2-[4-(Morpholinocarbonyl)-Perhydro-1,4-Diazepin-1-Yl]quinoline IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS

Anatomical and Physiological Factors Affecting Oral Drug Bioavailability in Rats, Dogs, and Humans

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