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Biomedical subjects

D K Walker

Publications and source records attributed to D K Walker.

At least 19 recordsLinked to original sources
PubMed2006

Effects of ractopamine and protein source on growth performance and carcass characteristics of feedlot heifers.

An experiment was conducted to determine the relationship between feeding ractopamine and different amounts of MP on growth and carcass characteristics of feedlot heifers. Seventy-two crossbred heifers (475 kg of initial BW) were fed individually a diet based on steam-flaked corn for ad libitum intake for 29 d. Heifers were implanted with 140 mg of trenbolone acetate and 14 mg of estradiol-17beta 60 d before the experiment. Treatments were arranged as a 2 x 3 factorial and included 0 or 200 mg of ractopamine-HCl (23 ppm)/ d, and urea, solvent soybean meal, or expeller soybean meal (ESBM) as the predominant protein supplement. The amounts of MP supplied by the urea, solvent soybean meal, and ESBM diets were 688, 761, and 808 g/ d, respectively, calculated according to level 1 of the NRC model. Body weights were obtained 1 d before ractopamine feeding and at slaughter. Blood samples were obtained 1 d before starting the experiment and 13 d later. Ractopamine improved ADG, efficiency of gain, carcass-adjusted ADG, and carcass-adjusted efficiency of gain (P < 0.01). For ADG, heifers demonstrated a ractopamine x protein source interaction (P < 0.05); heifers not fed ractopamine had greater ADG when fed ESBM than when fed urea, whereas for heifers fed ractopamine there were no differences (P > or = 0.10) among protein supplements. This interaction was not observed for carcass-adjusted ADG (P = 0.60). Final live weights (P = 0.02) and carcass weights (P = 0.01) were greater with ractopamine feeding. Carcass marbling scores and yield grades were not affected by ractopamine or protein source (P > or = 0.39). Plasma total alpha-amino N and glucose concentrations decreased more from pretreatment concentrations when heifers were fed ractopamine (P < 0.05). Feeding ractopamine to heifers for 28 d before slaughter improved ADG and efficiency of gain without any large effects on carcass characteristics. The MP supply does not need to be increased from that provided by finishing diets based on steam-flaked corn with urea as the primary N supplement to allow the maximal response to ractopamine by finishing heifers.

Adrenergic beta-Agonists↗
PubMed2005

Effects of dietary ruminally protected L-carnitine on plasma metabolites in sheep following a sub-lethal ammonia challenge.

In Experiment 1, lambs were randomly assigned to 0.25, 1.00, 2.50, 5.00 and 10.00 g/day of dietary ruminally protected L-carnitine (RPLC) and were allowed to adapt for 20 days. Plasma samples were obtained at 0, 120 and 240 min after RPLC feeding. Plasma L-carnitine (LC) concentrations increased (p<0.01) for all levels of RPLC treatment, however, no differences were observed due to level of RPLC or time. Plasma LC concentrations were 27.05 and 57.83 micromol/l for baseline and pooled RPLC treated sheep, respectively. In Experiment 2, lambs were randomly assigned to 0, 0.125, 1.06 and 2.0 g/day of RPLC and were adapted as in Experiment 1. Plasma was collected at 0, 15, 30, 60, 90, 180, 240 and 360 min after oral ammonia challenge (300 mg/kg BW urea). Plasma LC concentrations increased with treatment relative to control (p<0.01). Plasma LC concentrations were 35.7, 44.2, 60.5 and 65.7 micromol/l for the 0, 0.125, 1.06 and 2.0 g/day treatments, respectively. RPLC tended to decrease plasma ammonia at some time points (time x treatment; p=0.10). We conclude that RPLC increased plasma LC concentrations, but had only modest effects on plasma ammonia concentrations and had no effect on plasma urea or glucose concentrations.

Adaptation, Physiological↗
PubMed2004

The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development.

The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.

Drug Design↗
PubMed2003

The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.

Voriconazole is a new triazole antifungal agent with potent, wide-spectrum activity. Its pharmacokinetics and metabolism have been studied in mouse, rat, rabbit, dog, guinea pig, and humans after single and multiple administration by both oral and intravenous routes. Absorption of voriconazole is essentially complete in all species. The elimination of voriconazole is characterized by non-linear pharmacokinetics in all species. Consequently, pharmacokinetic parameters are dependent upon dose, and a superproportional increase in area under the curve is seen with increasing dose in rat and dog toxicology studies. Following multiple administration, there is a decrease in systemic exposure. This is most pronounced in mouse and rat, less so in dog, and not observed in guinea pig or rabbit. Repeat-dose toxicology studies in mouse, rat, and dog have demonstrated that induction of cytochrome P450 by voriconazole (autoinduction of metabolism) is responsible for the decreased exposure in these species. Autoinduction of metabolism is not observed in humans, and plasma steady-state concentrations remain constant with time. Voriconazole is extensively metabolized in all species. The major pathways in humans involve fluoropyrimidine N-oxidation, fluoropyrimidine hydroxylation, and methyl hydroxylation. Also, N-oxidation facilitates cleavage of the molecule, resulting in loss of the fluoropyrimidine moiety and subsequent conjugation with glucuronic acid. Major pathways are represented in animal species. The major circulating metabolite in rat, dog, and human is the N-oxide of voriconazole. It is not thought to contribute to efficacy since it is at least 100-fold less potent than voriconazole against fungal pathogens in vitro.

Adult↗
PubMed2002

Pharmacokinetics of selamectin following intravenous, oral and topical administration in cats and dogs.

The pharmacokinetics of selamectin were evaluated in cats and dogs, following intravenous (0.05, 0.1 and 0.2 mg/kg), topical (24 mg/kg) and oral (24 mg/kg) administration. Following selamectin administration, serial blood samples were collected and plasma concentrations were determined by high performance liquid chromatography (HPLC). After intravenous administration of selamectin to cats and dogs, the mean maximum plasma concentrations and area under the concentration-time curve (AUC) were linearly related to the dose, and mean systemic clearance (Clb) and steady-state volume of distribution (Vd(ss)) were independent of dose. Plasma concentrations after intravenous administration declined polyexponentially in cats and biphasically in dogs, with mean terminal phase half-lives (t(1/2)) of approximately 69 h in cats and 14 h in dogs. In cats, overall Clb was 0.470 +/- 0.039 mL/min/kg (+/-SD) and overall Vd(ss) was 2.19 +/- 0.05 L/kg, compared with values of 1.18 +/- 0.31 mL/min/kg and 1.24 +/- 0.26 L/kg, respectively, in dogs. After topical administration, the mean C(max) in cats was 5513 +/- 2173 ng/mL reached at a time (T(max)) of 15 +/- 12 h postadministration; in dogs, C(max) was 86.5 +/- 34.0 ng/mL at T(max) of 72 +/- 48 h. Bioavailability was 74% in cats and 4.4% in dogs. Following oral administration to cats, mean C(max) was 11,929 +/- 5922 ng/mL at T(max) of 7 +/- 6 h and bioavailability was 109%. In dogs, mean C(max) was 7630 +/- 3140 ng/mL at T(max) of 8 +/- 5 h and bioavailability was 62%. There were no selamectin-related adverse effects and no sex differences in pharmacokinetic parameters. Linearity was established in cats and dogs for plasma concentrations up to 874 and 636 ng/mL, respectively. Pharmacokinetic evaluations for selamectin following intravenous administration indicated a slower elimination from the central compartment in cats than in dogs. This was reflected in slower clearance and longer t(1/2) in cats, probably as a result of species-related differences in metabolism and excretion. Inter-species differences in pharmacokinetic profiles were also observed following topical administration where differences in transdermal flux rates may have contributed to the overall differences in systemic bioavailability.

Administration, Oral↗
PubMed2001

Absorption, distribution, metabolism, and excretion considerations in selection of orally active indole-containing endothelin antagonist.

A series of potent indole-containing endothelin antagonists were evaluated in rat pharmacokinetic studies as part of a rational drug design program. Early compounds in this series were found to show poor gastrointestinal absorption, limiting their utility as oral agents. Structural modifications and pharmacokinetic studies indicated that reducing the overall H-bonding potential, through a reduction in the number of H-bond donors and acceptors, could increase absorption of the molecules. There was a correlation between calculated H-bonding capacity and rate of permeability across Caco-2 monolayers for this series of compounds. Caco-2 permeability was also shown to be indicative of the estimated extent of absorption in rats. Balancing the requirements of absorption and systemic clearance lead to the selection of an alcohol-containing compound, compound 7a (single enantiomer of compound 7) that was moderately absorbed after oral administration and converted to an active acid metabolite, which itself was of low intrinsic clearance. Species differences were observed between the absorption of compound 7a in rat and dog and also in the extent of conversion to the acid metabolite. Absorption was estimated at 30% in rat and 100% in dog. Approximately 30% of the absorbed drug was converted to systemically available acid metabolite in rat, compared with only 3% in dog.

Administration, Oral↗
PubMed2000

How well does the questionnaire for identifying children with chronic conditions identify individual children who have chronic conditions?

BACKGROUND: The Questionnaire for Identifying Children With Chronic Conditions (QuICCC) is an instrument based on a conceptual noncategorical definition that uses parental responses to identify children with chronic conditions for epidemiological purposes. OBJECTIVES: To determine whether the QuICCC is sufficiently valid, sensitive, and specific to be used to identify individual children as having a chronic condition or disability; whether parents are accurate enough that their answers to QuICCC items can be accepted as valid; and what kinds of errors in classification occur when the QuICCC is used to identify children with chronic conditions. METHODS: The sample consisted of 424 children who were patients of 9 physicians in separate practice settings throughout New England. Each physician was briefly trained in the conceptual definition on which the QuICCC is based and then was asked to identify 25 children in his or her practice who met the definition and 25 children who did not meet the definition. The QuICCC was administered to the parents of these children by blinded interviewers via telephone. The QuICCC classification was compared with physician categorization. Discrepant cases were then followed up by asking physicians and parents to answer the original questions a second time. RESULTS: Complete data were available on 379 (89.4%) of 424 children. There was agreement on 89% (kappa = 0.78). The sensitivity was 94%; specificity, 83%; positive predictive value, 86%; and negative predictive value, 92%. Of the 42 discordant cases, 30 parent reports on the QuICCC qualified the child as having a chronic condition when the physician classified the child as being without such a condition. Fewer (n = 12) discrepancies occurred because physicians identified children with chronic conditions that the QuICCC failed to identify. When the questions were readministered at follow-up, physicians corrected errors in rating in 9 cases; mothers changed their answers in 5 instances. In 13 instances the issues were known to both parties and appeared to arise in the "gray zone" or boundary area, where there was disagreement over whether a particular child qualified using the theoretical definition. For 11 children identified as having a chronic condition only by the parent's responses to the QuICCC, physician report appeared to be inaccurate primarily due to the physician's lack of information. In 3 cases where the physician reported the child to have a chronic condition, but the parent did not, the physician appeared to be correct. Follow-up data were incomplete on 1 child. CONCLUSIONS: These data support the validity of parent-generated information for the evaluation of health status. Although these findings should be replicated, this study suggests that the QuICCC may be applicable also as a screening tool for individual child identification, provided that several sources of error are considered.

Child↗
PubMed2000

A sensitive method for the measurement of the novel pet endectocide, selamectin (UK-124,114), in dog and cat plasma by chemical derivatisation and high-performance liquid chromatography with fluorescence detection.

An analytical method has been developed for the novel pet endectocide, selamectin (USAN, UK-124, 114), in dog and cat plasma to facilitate pharmacokinetic profiling for this compound. The method involves solid phase extraction of the compound and internal standard from plasma followed by chemical derivatisation using triethylamine and trifluoroacetic anhydride. This reaction yields a highly fluorescent product and thus provides a sensitive assay. Using a sample volume of 1.0 ml for dog plasma the assay has been validated over a concentration range of 0.2-40 ng/ml. Due to smaller plasma volumes for cat plasma samples, the assay was validated over a concentration range of 1.0- 200 ng/ml using a sample volume of 0.2 ml. The analyte has been shown to be stable for 48 h at room temperature and through three freeze thaw cycles in dog plasma. The analytical method is highly specific and proved suitable for the analysis of selamectin in dog and cat plasma samples following doses of compound by parenteral and non-parenteral routes.

Animals↗
PubMed1999

Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man.

1. Pharmacokinetics were studied in mouse, rat, rabbit, dog and man after single intravenous and/or oral doses of sildenafil or [14C]-sildenafil (Viagra). 2. In man, absorption from the gastrointestinal tract was essentially complete. With the exception of male rat, Tmax occurred at approximately 1 h or less. Bioavailability was attenuated by pre-systemic hepatic metabolism in all species. 3. The volume of distribution was similar in rodents and humans (1-2 l/kg) but was greater in dog (5.2 l/kg), due to lower plasma protein binding (84 versus 94-96% respectively). 4. High clearance was the principal determinant of short elimination half-lives in rodents (0.4-1.3 h), whereas moderate clearance in dog and man resulted in longer half-lives (6.1 and 3.7 h respectively). Clearances were in agreement with in vitro metabolism rates by liver microsomes from the various species. 5. After single oral or intravenous doses of [14C]-sildenafil, the majority of radioactivity was excreted in the faeces of all species. No unchanged drug was detected in the excreta of man. 6. Five principal pathways of metabolism in all species were piperazine N-demethylation, pyrazole N-demethylation, loss of a two-carbon fragment from the piperazine ring (N,N'-deethylation), oxidation of the piperazine ring and aliphatic hydroxylation. Additional metabolites arose through combinations of these pathways. 7. Sildenafil was the major component detected in human plasma. Following oral doses, AUC(infinity) for the piperazine N-desmethyl and piperazine N,N'-desethyl metabolites were 55 and 27% that of parent compound respectively.

Administration, Oral↗
PubMed1999

The new St. Jude Medical regent mechanical heart valve: laboratory measurements of hydrodynamic performance.

BACKGROUND AND AIM OF THE STUDY: The St. Jude Medical (SJM) mechanical heart valve was the first bileaflet valve with leaflets and orifice all fabricated from pyrolytic carbon. In 1992, a supra-annular cuff configuration, the SJM mechanical heart valve Hemodynamic Plus Series (HP), was introduced, which gave a one-size gain in orifice area over the standard valve. In a continuing effort to improve hydrodynamic performance, a new enhanced configuration of the mechanical valve - the SJM Regent valve - has been developed. The blood-contacting components of the SJM Regent valve have the same design features as those of the standard or HP valve, but the orifice lumen area has been increased, without compromising structural integrity, by a shift in the cuff-retaining orifice rims. METHODS: Valve performance has been measured using a laboratory simulation of the left heart system. Three samples of both valve types (SJM Regent, HP) for sizes 17 mm to 27 mm, were tested at a cardiac output of 5 l/min. Supplementary steady-flow measurements were made at flow rates between 5 and 30 l/min. Pressure and flow signals were recorded and several performance parameters, including pressure gradient, effective orifice area (EOA), insufficiency (regurgitant volume as a percent of forward flow volume) and energy loss, were computed. RESULTS: All sizes of the SJM Regent valve showed improved hydrodynamic performance compared with the HP valve. For the small sizes (17, 19, 21 mm), the pressure gradient of the SJM Regent decreased by 37%, 36% and 39%, respectively; the EOA increased by 22%, 22% and 21%; and the total transaortic energy loss decreased by 33%, 31% and 31% compared with the HP valve. The regurgitation for both valves ranged between 4% and 8% of forward flow volume over the 17-27 mm size range. CONCLUSIONS: Hydrodynamic measurements confirm the gain of the SJM Regent valve over the HP valve that is expected based on the increased geometric orifice area. Given its basic similarity of design, but with an increased EOA as demonstrated in vitro, the SJM Regent valve is anticipated to provide an increased level of clinical benefit.

Biocompatible Materials↗
PubMed1998

Automated 96-well solid phase extraction for the determination of doramectin in cattle plasma.

Automated standard and sample preparation have been coupled with 96-well solid phase extraction (SPE) technology to produce a cost effective, high throughput system for the analysis of drugs in biological media. The system was originally designed using the Packard Multiprobe 104DT robotic sample processor (RSP) to improve throughput for the assay of doramectin in cattle plasma, and the assay has since been validated (0.5-100 ng ml[-1]) using the Tecan Genesis RSP 150/8. The robotic processor conducts all liquid handling procedures involved in sample extraction. These comprise preparation of calibration standards in plasma, dispensing and diluting of plasma samples and addition of internal standard. In addition, the robot primes the 96-well SPE block, applies calibration standards and samples, draws the mixtures through the 96-well SPE block, and finally washes the block ready for manual elution. The doramectin assay involves high-performance liquid chromatography (HPLC) with fluorescence detection, and requires the sample extracts to be derivatised prior to analysis. The derivatisation procedure is performed manually in situ in the polypropylene deep 96-well block into which the samples have been eluted from the SPE-block. The derivatised samples are taken directly from the deep well block and injected into the HPLC for analysis. This type of batch processing keeps sample transfer to a minimum. Automated sample preparation, in combination with the use of 96-well technology, has reduced both cost and effort required in the analysis of doramectin in cattle plasma samples, and has resulted in improved sample throughput.

Animals↗
PubMed1997

Monitoring health care for children with chronic conditions in a managed care environment.

OBJECTIVE: Children with chronic health conditions face special issues in their interactions with managed care. These children often require additional and more varied services than do other children. Managed care plans increasingly include these children, especially with the growth of Medicaid managed care. This article examines the special issues facing children with chronic conditions and develops strategies for monitoring their care in managed care settings. METHODS: The project staff conducted an extensive review of the research and policy literature related to managed care and the special needs of families with children with chronic conditions. The project also reviewed current and proposed plans of federal, state, and private groups for monitoring and, working with parents and other outside groups, identified key issues to consider in developing monitoring plans. RESULTS: The relative rarity of many childhood conditions and the complex interactions among child, family, and community over time make assessment of their care difficult. We describe these child and family characteristics, outline essential features and domains for monitoring systems, and describe population-based and plan-based monitoring systems to assess managed care for these children and their families. CONCLUSIONS: Monitoring for children with chronic conditions in managed care arrangements will require public health agencies and health providers to define populations systematically, assess across a variety of conditions, and monitor several domains central to the health of these families.

Adolescent↗
PubMed1996

Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics.

Drug metabolism input to the discovery process had historically been on an empirical case-by-case basis, since, detailed descriptors of the effect on pharmacokinetics of a change in structure or physicochemical property were not available. Considerable advances have been made in recent years, such that basic rules can be applied to predict the behavior of a compound in man based on physicochemistry and structure. This is particularly true in the areas of absorption, distribution, and clearance. In particular, knowledge of the reactions catalyzed by the enzymes of drug metabolism, including the cytochrome P450 super family, can be used in the design of new chemical entities, together with the usual pharmacological-derived SAR. The combination of both pharmacokinetics and pharmacodynamics at the discovery stage leads to drugs with optimum performance characteristics. Such drugs are easier to develop, representing a huge saving in resources. Moreover, the marketed compound is much more likely to find high clinical utilization. This review uses dofetilide, fluconazole, and amlodipine to highlight the multifaceted consequences of changing chemical structure, in terms of drug disposition, and reinforces these principles with examples from the literature.

Absorption↗
PubMed1996

Effects of streptozotocin-induced diabetes and insulin treatment on substance P of the rat arterial wall.

Substance P (SP) is present in perivascular nerves throughout the mammalian vasculature. Reports of diminished SP levels in nerve and gastrointestinal tissues of diabetic rats led us to examine SP-like immunoreactivity (SP-LI) in large arteries by RIA. Six weeks after inducing diabetes with streptozotocin (STZ), SP-LI was measured in the thoracic aorta, abdominal aorta, and the proximal superior mesenteric artery. In diabetics we measured a doubling (P<0.01) of SP-LI in all three artery wall preparations. This finding was verified in a second experiment which included a subset of diabetics treated daily with insulin for the sixth week of the holding period. Again, we measured a two-fold or greater increase of SP-LI (P<0.01-0.05) in arteries from the diabetics and found that insulin treatment significantly reduced SP-LI (P<0.05). In contrast to reports of diminished SP content in other tissues of diabetic rats, our findings demonstrate that the artery wall experiences at least a two-fold increase of SP-LI in the diabetic state. Furthermore, this elevation of SP-LI is reduced by insulin. We speculate that these changes of arterial wall SP-LI may contribute to altered regulation of the vascular system in the diabetic state.

Animals↗
PubMed1996

Pharmacokinetics of a series of bis(methanesulphonamido-arylalkyl)amines in the beagle dog.

1. The pharmacokinetics of three closely related analogues of dofetilide have been investigated in the beagle dog. These have been compared with those of dofetilide and related to physicochemical properties and structural features of the molecules. 2. Following intravenous administration, the four compounds exhibit elimination half-lives ranging from 4.6 to 19 h. This range is due to changes in both volume of distribution and plasma clearance across the series. 3. In vitro plasma protein shows a relationship to lipophilicity within this series. Protein binding increasing from 54% for dofetilide, the least lipophilic compound (log D7.4 = 0.73) to 92% for the most lipophilic analogue (log D7.4 = 2.07). There is a trend for a decrease in the volume of distribution with increased plasma protein binding. 4. Plasma clearance values range from 2.4 to 10.2 ml/min/kg and are comprised of renal and non-renal components. Renal clearance ranges fro 0.11 to 2.9 ml/min/kg and shows an inverse correlation with and lipophilicity of the compounds. Values for the renal clearance of unbound drug suggest that only the most lipophilic derivative (III), has sufficient membrane affinity to undergo tubular reabsorption. 5. Non-renal clearance of either total or free drug shows no relationship with lipophilicity. Highest values are observed for the two compounds with a methyl substituent on the tertiary amine and lowest values for the two compounds in which the tertiary amine is incorporated into a 7-membered ring. In vitro metabolism in dog liver microsomes also shows increased lability for the two N-methyl compounds. The N-desmethyl metabolite is the major product in both cases.

Animals↗
PubMed1996

Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data.

Dofetilide, a class III antidysrhythmic agent, undergoes both renal and metabolic clearance. Characterization of the metabolism in vitro allows explanation of species differences, whereas identification of the human enzymes involved permits assessment of potential drug interaction. In liver microsomes, the rate of oxidative metabolism of dofetilide is in the order: male rat > female rat > dog > humans, which correlates with the metabolic clearance seen in vivo. In vitro products of oxidative metabolism, formed by N-dealkylation, are the same as those formed in vivo, with the N-desmethyl being the major product. This route of dofetilide metabolism is mediated by cytochrome P450 (CYP). In humans, N-demethylation has a high KM of 657 +/- 116 microM, indicating low affinity for the enzyme's active site. In a number of human liver microsomal preparations, this rate correlated (r = 0.903) with the activity of CYP3A4. There was no correlation with the activities of other isozymes. Specific isozyme inhibitors also indicated the involvement of CYP3A4, with partial inhibition being observed with ketoconazole and troleandeomycin, whereas the activator, alpha-naphthaflavone, caused increased turnover. No inhibition was observed with specific inhibitors or competing substrates for other isozymes. Dofetilide did not significantly inhibit CYP2C9, CYP2D6, or CYP3A4 at concentrations up to 100 microM in vitro. In contrast, amiodarone (IC50, 25 microM) and flecainide (49 microM) inhibited CYP2C9 and quinidine (0.26 microM), and flecainide (0.44 microM) inhibited CYP2D6. Many antidysrhythmic drugs have active, circulating metabolites, complicating the relationship of dose and clinical response. In vitro pharmacology studies allow assessment of the potential contribution to the pharmacological profile by metabolites. Potency of dofetilide and metabolites has been compared for class III (K+ channel blockade) and class I (Na+ channel blockade) antidysrhythmic activities. Three of the metabolites of dofetilide displayed class III activity, but at concentrations at least 20-fold higher than dofetilide. Dofetilide N-oxide showed class I activity, but only at high concentration. Neither resting membrane potential or action potential amplitude were affected by any metabolite. This lack of biologically relevant activity is in accord with the close correlation between plasma concentrations of dofetilide and pharmacological response.

Action Potentials↗