Pharmacokinetics and metabolism of a selective PDE5 inhibitor (UK-343,664) in rat and dog

Walker, Don K.; Beaumont, Kevin; Comby, Pierre; Evans, Karen; Gedge, Jenny I.; Halliday, R C; Roffey, S. J.; Wright, Patricia

doi:10.1080/00498250110056522

Cited by 13 publications

(27 citation statements)

References 7 publications

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“…Following intravenous administration of radioactive UK-343,664 to rats and dogs, excretion studies have shown that only 10% of the drug was eliminated as parent compound. 51 These findings show metabolism as the main mechanism of drug elimination, and extrahepatic clearance plays a lesser role in the total elimination. 51 These findings also indicate that a good prediction of the in vivo liver clearance would give a reasonable estimation of the total systemic clearance.…”

Section: ■ Materials and Methodsmentioning

confidence: 96%

“…51 These findings show metabolism as the main mechanism of drug elimination, and extrahepatic clearance plays a lesser role in the total elimination. 51 These findings also indicate that a good prediction of the in vivo liver clearance would give a reasonable estimation of the total systemic clearance. Several in vitro models have been established for the prediction of liver clearance.…”

Section: ■ Materials and Methodsmentioning

confidence: 96%

“…These tests include data collected from the literature, 38,50,51 or unpublished data provided by Pfizer Global Research and Development (Sandwich, U.K.). In addition, some parameters were obtained experimentally in our laboratory as described below.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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In Silico Modeling for the Nonlinear Absorption Kinetics of UK-343,664: A P-gp and CYP3A4 Substrate

et al. 2012

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The aim of this work was to extrapolate in vitro and preclinical animal data to simulate the pharmacokinetic parameters of UK-343,664, a P-glycoprotein (P-gp) and CYP3A4 substrate, in human. In addition, we aimed to develop a simulation model to demonstrate the involvement and the controversial complex interaction of intestinal P-gp and CYP3A4 in its nonlinear absorption, first-pass extraction, and pharmacokinetics using the advanced compartmental absorption and transit (ACAT) model. Finally, we aimed to compare the results predicted from the model to the reported findings in human clinical studies. In situ perfusion, allometric scaling, PBPK Rodger mechanistic approach, in vitro metabolism, and fitting to in vivo data were used to mechanistically explain the absorption, distribution and metabolism, respectively. GastroPlus was used to build the integrated simulation model in human for UK-343,664 to mechanistically explain the observed clinical data at 30, 100, 200, 400, and 800 mg oral doses. The measured in vitro value for CYP3A4 K(m) (465 μM) in rCYPs was converted to units of μg/mL, corrected for assumed microsomal binding (17.8%) and applied to all metabolic processes. The measured in vitro values of V(max) for CYP3A4 (38.9 pmol/min/pmol), 2C8, 2C9, 2C19, and 2D6 were used along with the in vitro CYP3A4 K(m) to simulate liver first pass extraction and systemic clearance. The measured in vitro values of V(max) for CYP3A4 and 2D6 were used along with the in vitro CYP3A4 K(m) to simulate gut first pass extraction. V(max) and K(m) values for P-gp were obtained by fitting to in vivo data and used to simulate gut efflux transport activity. Investigation of the interaction mechanism of P-gp and CYP3A4 in the intestine was achieved by comparing the influence of a virtual knockout of P-gp or gut metabolism on the fraction absorbed, fraction reaching the portal vein, and fraction metabolized in the gut. Comparison between simulation and in vivo results showed that the in silico simulation provided a mechanistic explanation of the observed nonlinear absorption kinetics of UK-343,664 in human following its administration in the range of 30-800 mg as oral solutions. The simulation results of the pharmacokinetic parameters, AUC and C(max), by GastroPlus were comparable with those observed in vivo. This simulation model is one possible mechanistic explanation of the observed in vivo data and suggests that the nonlinear dose dependence could be attributed to saturation of both the efflux transport by P-gp and the intestinal metabolism. However, the concentration ranges for either protein saturation did not overlap and resulted in much greater than dose proportional increases in AUC. At low doses, producing intraenterocyte concentrations below the fitted value of K(m) for P-gp, the influence of P-gp appears to be protective and results in a lower fraction of gut 3A4 metabolism. At higher doses, as P-gp becomes saturated the fraction of gut 3A4 extraction increases, and eventually at the highest doses, where 3A4 becomes satur...

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Section: ■ Materials and Methodsmentioning

confidence: 96%

Section: ■ Materials and Methodsmentioning

confidence: 96%

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In Silico Modeling for the Nonlinear Absorption Kinetics of UK-343,664: A P-gp and CYP3A4 Substrate

et al. 2012

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“…The hydroxylated metabolites are subjected to Phase II metabolism (conjugation with glucuronic and/or sulphuric acids). Oxidation of the piperazine ring and the identi®cation of mono-and di-hydroxypiperazine metabolites have been previously reported for sildena®l (Walker et al 1999), UK-343,664 (Walker et al 2001) and CP93,393 (Prakash and Soliman 1997). The stability of carbinolamines in aqueous media has been reported by Urbansky (2000) and stable carbinolamine metabolites of a number of drugs have also been isolated (Jackson et al 1991, Lang et al 1997, Upthagrove and Nelson 2001.…”

Section: Cyclizine Metabolismmentioning

confidence: 89%

Biotransformation of cyclizine in greyhounds. 1: identification and analysis of cyclizine and some basic metabolites in canine urine by gas chromatography-mass spectrometry

Dumasia¹,

Grainger²,

Houghton³

2002

Xenobiotica

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1. The partial in vivo biotransformation of Marezine [(cyclizine.HCl); 1-diphenylmethyl-4-methylpiperazine hydrochloride] in the racing greyhound and the excretion of the unconjugated and conjugated (Phase II) basic metabolites of cyclizine in canine urine are reported. 2. Using copolymeric bonded mixed-mode solid-phase extraction cartridges, the basic isolates from both unhydrolysed and enzyme hydrolysed urine samples were isolated, derivatized as trimethylsilyl ethers and analysed by positive-ion electron ionization gas chromatography-mass spectrometry (EI(+)-GC-MS). Selected samples were analysed by positive-ion methane chemical ionization (CI(+))-GC-MS to aid structure elucidation of the putative metabolites. 3. Cyclizine was the major component excreted in post-administration urine. Five substrate-related basic compounds (M1--> M5) were tentatively identified by EI(+)- and CI(+)-GC-MS. The major Phase I metabolite was identified as norcyclizine [1-diphenylmethylpiperazine] (M1), the other metabolites (M2 --> M5) were tentatively identified as monohydroxylated products based on MS data. 4. Cyclizine and the N(4)-desmethyl metabolite (M1) are excreted unconjugated; the other four hydroxylated metabolites are excreted as Phase II conjugates (glucuronides and/or sulphates). Structures of the putative basic metabolites are presented. At least four other basic metabolites were also detected in post-administration urine, but could not be characterized from GC-MS data. 5. All unhydrolysed post-administration urine samples were analysed by selected ion monitoring EI(+)-GC-MS to quantify cyclizine and norcyclizine (M1) using authentic cyclizine as the analyte and chlorcyclizine as the internal standard. The level of M1 is expressed as 'cyclizine equivalents'. The duration of urinary elimination of cyclizine and M1 was obtained from their excretion profiles. 6. From these studies, cyclizine and norcyclizine (M1) would be the target compounds of choice in the development of screening and confirmatory methods for the detection of cyclizine administration to racing greyhounds. Information on any of the other metabolites may also be of some value for confirmatory analysis.

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“…65 In human volunteers, 66 this clinical candidate did not exhibit dose proportionality over the dose range 30-800 mg. Over this 27-fold dose range, C max and AUC t increased 247-and 287-fold respectively. Based on studies with human P450 enzymes it was concluded that saturation of first-pass metabolism alone was not likely to account for this observation.…”

Section: E F F O R T S T O D I S C O V E R P D E 5 I N H I B I T O mentioning

confidence: 98%

Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: Attaining selectivity versus PDE6

Pissarnitski¹

2005

Medicinal Research Reviews

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The role of phosphodiesterase type 5 (PDE5) in the mechanism of male erection has been well understood, and several drugs inhibiting this enzyme are being used for the treatment of erectile dysfunction (ED). Discovery of inhibitors with improved selectivity versus other PDE isozymes could lead to drugs with improved safety profile. Achievement of selectivity versus PDE6, co-inhibition of which results in disturbances of color perception, remains the most challenging aspect of current drug discovery programs. The present review describes several case studies, where significant (>100 fold) selectivity versus PDE6 has been attained via investigation of structure-activity relationships (SAR). Special attention is given to the chemical routes leading to novel chemotypes and allowing efficient exploration of their SAR's. Strategies for attaining inhibitor selectivity discussed below may be applicable for other drug discovery programs.

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Pharmacokinetics and metabolism of a selective PDE5 inhibitor (UK-343,664) in rat and dog

Cited by 13 publications

References 7 publications

In Silico Modeling for the Nonlinear Absorption Kinetics of UK-343,664: A P-gp and CYP3A4 Substrate

In Silico Modeling for the Nonlinear Absorption Kinetics of UK-343,664: A P-gp and CYP3A4 Substrate

Biotransformation of cyclizine in greyhounds. 1: identification and analysis of cyclizine and some basic metabolites in canine urine by gas chromatography-mass spectrometry

Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: Attaining selectivity versus PDE6

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