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Biomedical subjects

G R Wilkinson

Publications and source records attributed to G R Wilkinson.

At least 109 records · Page 6Linked to original sources
PubMed1986

Furosemide kinetics and dynamics in patients with cirrhosis.

Factors that influence intersubject variability in response to furosemide have been investigated in normal subjects and patients with cirrhosis. Furosemide pharmacokinetics and pharmacodynamics were measured in eight normal subjects and 14 patients with cirrhosis, eight of whom were resistant to diuretic therapy. Furosemide renal clearance decreased in proportion to creatinine clearance, whereas nonrenal clearance and volume of distribution were unchanged. These pharmacokinetic changes were, however, minimal and resulted in an only marginal alteration in the plasma concentration-time curve. The maximal rate of urinary sodium excretion decreased with reductions in creatinine clearance (r = 0.77). However, the extent of reduction in urinary excretion of sodium was proportionally greater than the reduction in creatinine clearance, whereas the rate of urinary furosemide excretion required to achieve 50% of maximal response did not change. Furosemide's pharmacokinetics were not, therefore, appreciably altered by cirrhosis. However, cirrhosis was associated with a reduction in pharmacodynamic response to this diuretic.

Adult↗
PubMed1986

Encainide disposition in patients with renal failure.

The antiarrhythmic agent encainide undergoes extensive presystemic biotransformation to form O-desmethylencainide (ODE) and 3-methoxy-ODE (MODE) in subjects who exhibit the extensive metabolizer (EM) phenotype for debrisoquin 4-hydroxylation. These metabolites contribute significantly to the overall antiarrhythmic activity and are extensively excreted in the urine. Therefore, the effects of renal impairment on the disposition of encainide and its metabolites were studied in seven EM patients with renal failure and compared with those in eight healthy normal subjects of the same phenotype. After a single dose of encainide, its systemic and oral clearances were significantly lower and its elimination t1/2 was shorter in patients with renal failure than in healthy volunteers. This shortening was explained by a significant reduction in steady-state volume of distribution in renal failure. After chronic dosing to steady state, quantitatively similar changes were seen. Chronic oral dosing produced 80% higher levels of ODE (the most pharmacodynamically active metabolite) and 167% higher levels of MODE as compared with healthy volunteers. The prolongations in ECG intervals were similar in the two groups despite the higher encainide dose in the normal subjects. In conclusion, patients with renal failure will require lower doses of encainide because of both reduced encainide clearance and increased accumulation of active metabolites.

Acute Kidney Injury↗
PubMed1986

Encainide disposition in patients with chronic cirrhosis.

The antiarrhythmic agent encainide undergoes extensive first-pass hepatic metabolism after oral dosing. The active metabolites O-desmethylencainide and 3-methoxy-O-desmethylencainide are formed in subjects who are extensive metabolizers (EMs), a phenotypic trait that cosegregates with that of debrisoquin. Because of the possibility that drug metabolism is altered by liver dysfunction, the disposition of encainide and its metabolites was studied in six such EMs with cirrhosis and compared with that in eight normal subjects of the same phenotype. Patients with cirrhosis had lower systemic and oral clearances of encainide, resulting in a threefold increase in oral bioavailability. The plasma concentration of encainide was significantly higher among the patients with cirrhosis, whereas the plasma levels of the respective metabolites were comparable with those in normal subjects, resulting in no change in the patient's ECG intervals. Encainide is, therefore, an example of a drug in which cirrhosis causes a three- to fourfold increase in parent drug concentrations. However, because no change occurs in the levels of the pharmacologically active metabolites, dosage adjustment is probably not required in patients with cirrhosis.

Administration, Oral↗
PubMed1986

Reduction of liver plasma flow by caffeine and theophylline.

Caffeine and theophylline block the vasodilating effects of adenosine and may act to enhance sympathoadrenal discharge and activate the renin-angiotensin system. To determine if these methylxanthines might thereby have effects on regional blood flow, we studied the influence of caffeine and theophylline on apparent liver plasma flow (LPF) in normal subjects as assessed by indocyanine green clearance. Oral caffeine, 250 mg, reduced LPF by 19% from 630 +/- 150 to 510 +/- 120 ml/min (P less than 0.001). Intravenous theophylline (4.3 mg/kg) reduced LPF by 15% from 550 +/- 50 to 470 +/- 90 ml/min (P less than 0.05). These methylxanthine-induced falls in LPF may alter the disposition of concomitantly administered drugs. Because of their widespread use in Western society, caffeine and theophylline may be major determinants of liver blood flow in the general population. They may therefore prolong the t1/2 and increase steady-state levels of hepatically eliminated drugs.

Adenosine↗
PubMed1986

Co-inheritance of the polymorphic metabolism of encainide and debrisoquin.

O-demethylation of the investigational antiarrhythmic encainide was found to be correlated with the genetically determined hydroxylation of debrisoquin in 20 randomly selected and unrelated subjects and in five members of one family. Extensive metabolizers of debrisoquin had a mean (+/- SD) encainide elimination t1/2 of 1.19 +/- 0.98 hours (range 0.25 to 3.4 hours). Poor metabolizers of debrisoquin (two normal subjects and three family members) had a mean t1/2 of 13.2 +/- 0.73 hours (range 7.8 to 22.4 hours). The elimination rate constant of encainide and the fractional excretion of O-desmethyl encainide in urine were linearly related to the fractional urinary excretion of 4-hydroxy-debrisoquin. Poor metabolizers could be identified after a 50 mg dose of encainide by the fractional excretion of O-desmethyl encainide in urine or the absence of (1) measurable ECG changes or (2) O-desmethyl encainide in plasma. The correlation between excretion of O-desmethyl encainide and 4-hydroxy-debrisoquin suggests that significant numbers of the caucasian population (7% to 9%) are likely to be poor metabolizers of encainide and to have markedly different pharmacokinetics and plasma concentration-response relationships than extensive metabolizers.

Administration, Oral↗
PubMed1986

Oxidative metabolism of encainide: polymorphism, pharmacokinetics and clinical considerations.

The 8-h urinary metabolic profiles of encainide and its oxidized metabolites, O-desmethyl- (ODE), 3-methoxy-O-desmethyl- (MODE), N-desmethyl- (NDE) and N, O-didesmethyl- (DDE) encainide were studied in a group of 112 normal Caucasians. Nine of these subjects (8%) were defective in their ability to 4-hydroxylate debrisoquine. The cumulative frequency distribution of the 8-h recovery ratio of encainide/ODE indicated two distinct populations in complete concordance with the debrisoquine phenotyping. The subjects with an 'extensive metabolizer' (EM) phenotype had a ratio from 0.003 to 0.9 whereas the PM group had values from 7.4 to 48. In addition, no MODE was detected in the urine from 'poor metabolizers' (PM). The oxidative metabolism of encainide, specifically the O-demethylation pathway, is, therefore, polymorphically distributed and controlled by the same genetic factor(s) that determine the 4-hydroxylation of debrisoquine. In EM subjects, ODE and MODE are the major metabolites in plasma and their concentrations are much greater than those of unchanged drug. As ODE is a more potent antiarrhythmic agent than encainide and MODE is at least equipotent, these metabolites significantly contribute to the overall antiarrhythmic effect in EM patients. The low plasma concentrations of ODE and MODE in PM subjects would be expected to result in inefficacious therapy when usual doses of encainide are administered. However, in such individuals, chronic oral therapy results in accumulation of unmetabolized encainide to far higher levels than in EM subjects. As encainide itself has intrinsic antiarrhythmic activity at these concentrations, this generally results in the desired clinical response. Despite pronounced interphenotypic differences in encainide's disposition and pharmacokinetics, the polymorphic oxidative metabolism appears to have limited consequences for the drug's clinical efficacy.

Adolescent↗
PubMed1985

Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism.

Two forms of cytochrome P-450 were purified to apparent homogeneity from several different preparations of human liver microsomes. One form, designated P-450DB, had relatively high catalytic activity towards the drugs debrisoquine, sparteine, bufuralol (both the (+)- and (-)-isomers), encainide, and propranolol and appears to be the enzyme involved in the polymorphic distribution of oxidative activities towards these substrates in humans. The other form, designated P-450PA, had relatively high phenacetin O-deethylase activity and appears to be involved in the variation of this activity among humans. Polyclonal antibodies raised to the two enzymes were specific for the antigens as judged by immunoelectrophoresis and immuno-inhibition studies. The two enzymes and their activities were distinguished by chromatographic separation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, amino acid composition, immuno-inhibition studies, and steady-state kinetic assays. Immunochemical studies suggest that each form represents only a small fraction of the total cytochrome P-450 in human liver microsomes. These biochemical studies provide a basis for better understanding the mechanisms which underlie genetic polymorphisms involving P-450 cytochromes in humans.

Amino Acids↗
PubMed1985

Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations.

Interethnic differences in debrisoquin and mephenytoin hydroxylation have been compared between normal white (n = 183) and Japanese (n = 100) subjects with the 8-hour urinary metabolic ratio of debrisoquin and the urinary S/R enantiomeric ratio of mephenytoin to identify extensive (EM) and poor (PM) metabolizers. In white subjects the frequency of PMs was 8.7% and 2.7% for debrisoquin and mephenytoin, respectively. In contrast, in Japanese subjects no PMs of debrisoquin were identified, while the incidence of PMs of mephenytoin was 18%. These substantial differences (P less than 0.001) in polymorphic distributions of oxidative drug metabolizing ability have implications for interethnic efficacy and toxicity of drugs and other xenobiotics that are metabolized by the involved cytochrome P-450 isozymes.

Administration, Oral↗
PubMed1985

Effects of age on meperidine disposition.

Elderly patients appear to be more sensitive to meperidine than younger ones; however, the contributions of altered dynamic and kinetic factors are not clear. Accordingly, seven healthy normal men aged 60 to 79 yr were simultaneously given 25 mg meperidine HCl intravenously and the same dose of deuterium-labeled drug either orally or intramuscularly (deltoid). Blood and urine samples collected over 24 hr were analyzed by gas chromatography-mass spectrometry and kinetic data were compared to those previously obtained in a young cohort. Systemic clearance (8.61 +/- 2.22 ml/min/kg), apparent oral clearance (17.5 +/- 5.5 ml/min/kg), terminal t1/2 (6.98 +/- 1.86 hr), and the blood/plasma concentration ratio (0.97 +/- 0.12) in the elderly did not differ from those in younger subjects. In the elderly, however, the initial (2.4 +/- 0.8 l/kg) and the steady-state (4.6 +/- 0.9 l/kg) volumes of distribution were 300% and 135% values in the young. No age differences were found in absorption profiles or bioavailability after oral (F = 0.49 +/- 0.08) or intramuscular (F = 0.94 +/- 0.04) dosing. It appears that age-related alterations in drug disposition per se do not account for changes in clinical efficacy of meperidine in the elderly.

Administration, Oral↗
PubMed1985

Phenotypic differences in mephenytoin pharmacokinetics in normal subjects.

The urinary metabolic profile of mephenytoin and its oxidative metabolites indicates significant stereoselective metabolism of its two enantiomers. Also, polymorphic oxidation, which is present in about 2 to 5% of the Caucasian population, has been demonstrated by an impaired ability to 4-hydroxylate this anticonvulsant. In order to determine the consequences of such metabolism, the plasma concentration/time profiles of the enantiomers of mephenytoin and its N-demethylated metabolite, phenylethylhydantoin (PEH), were investigated after a single p.o. dose of racemic mephenytoin in normal subjects with different metabolizing ability for mephenytoin [extensive metabolizer (EM) vs. poor metabolizer (PM) phenotypes]. In the EM subjects, the disposition of S- and R-mephenytoin was markedly different with a 100- to 200-fold difference in mean oral clearance (4.7 vs. 0.027 liters/min) and a 30- to 40-fold difference in elimination half-life (2.1 vs. 76 hr). In these same subjects, R-PEH concentrations significantly accumulated over several days and then very slowly declined with an apparent half-life of about 200 hr. Plasma levels of S-PEH were essentially negligible. In contrast, the stereoselective elimination of mephenytoin was reduced markedly in subjects of the PM phenotype, with the disposition of the S-enantiomer being the same as that for R-mephenytoin, which in turn was similar to that observed for this enantiomer in EMs. Almost comparable plasma levels of S- and R-PEH were also present in PMs. Only a small amount (less than 5%) of unchanged mephenytoin was excreted in the urine regardless of phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism.

Genetic polymorphism in oxidative drug metabolism is perhaps best exemplified in the case of debrisoquine 4-hydroxylase activity, where the incidence of deficient metabolism ranges from 1% to 30% in various populations and this defect is also linked to an impaired ability to metabolize a number of other drugs effectively. Sprague-Dawley (SD) rats possess this activity, but females of the DA strain do not, although total cytochrome P-450 (P-450) levels are similar. We have purified, by using debrisoquine 4-hydroxylase activity as an assay, a minor P-450 to electrophoretic homogeneity from male SD rats and designate this as P-450UT-H. P-450UT-H differs from eight other purified rat liver P-450s as judged by peptide mapping and immunochemical analysis and thus appears to be isozymic with these other P-450s. P-450UT-H exhibited considerably more debrisoquine 4-hydroxylase activity than any of the other purified P-450s and, on a total P-450 basis, more than total microsomal P-450. Antibodies raised against P-450UT-H specifically recognized P-450UT-H and inhibited more than 90% of the debrisoquine hydroxylase activity present in SD rat liver microsomes. The level of P-450UT-H in SD rat liver microsomes accounted for less than 10% of the total P-450, as judged by immunochemical quantitation. These assays also indicated that the level of P-450UT-H in female DA rat liver microsomes is only about 5% of that in male or female SD rat liver microsomes, consonant with the view that deficiency of this form of P-450 is responsible for the defective debrisoquine 4-hydroxylase activity in the former animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Direct enantiomeric resolution of mephenytoin and its N-demethylated metabolite in plasma and blood using chiral capillary gas chromatography.

A gas chromatographic method was developed for the determination of the R- and S- enantiomers of the anticonvulsant, mephenytoin, and its N-demethylated metabolite, 5-phenyl-5- ethylhydantoin ( PEH ), in plasma and blood. Direct enantiomeric separation of mephenytoin and its internal standard was obtained using a chiral capillary column ( Chirasil -Val) followed by nitrogen specific detection. However, resolution of the enantiomers of PEH and its internal standard required propylation at the 3-position of the hydantoin ring prior to analysis. Similar linear and reproducible standard curves were obtained from both plasma and blood over the concentration range 50 ng/ml to 5 micrograms/ml, and above 100 ng/ml the reproducibility was less than 8% (coefficient of variation). Pronounced stereoselective differences in the plasma concentration--time curves for both mephenytoin and PEH were observed in a normal subject who received a single oral dose of 300 mg racemic mephenytoin. The peak plasma level of S-mephenytoin was only one-fifth that of the R-enantiomer and its elimination half-life was less than 3 h compared to over 70 h for R-mephenytoin. Similarly, S- PEH levels were barely detectable whereas concentrations of R-metabolite steadily increased over 4-6 days before slowly declining.

Anticonvulsants↗
PubMed1984

Polymorphic ability to metabolize propranolol alters 4-hydroxypropranolol levels but not beta blockade.

The ability to hydroxylate debrisoquine is known to be polymorphically distributed, with about 8% to 9% of the North American Caucasian population being poor metabolizers. We have shown that the ability to 4-hydroxylate propranolol is also polymorphically determined and that it cosegregates with ability to metabolize debrisoquine, such that poor debrisoquine metabolizers produce much less 4-hydroxypropranolol (4-OH propranolol) than do extensive metabolizers. There was no significant difference, however, between plasma propranolol concentrations after either single or multiple doses in the two groups. Despite the substantial difference in production of the pharmacologically active 4-OH metabolite, no difference was seen in the extent of beta-blockade induced in the extensive and poor metabolizers, which implies that 4-OH propranolol does not contribute substantially to beta-blockade.

Adult↗
PubMed1984

Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism.

The ability of normal subjects to hydroxylate mephenytoin (100 mg) or debrisoquine (10 mg) after oral dosing was investigated in 156 unrelated Caucasians living in middle Tennessee. Urinary recovery of 4-hydroxymephenytoin (4-OH-M) and the urinary S:R enantiomeric ratio of mephenytoin measured in an 8-hr urine sample were investigated as phenotypic traits for mephenytoin, and the urinary metabolic ratio of debrisoquine was used to determine the debrisoquine hydroxylase phenotype. Both urinary 4-OH-M and the S:R ratio of mephenytoin discriminated between extensive (EM) and poor (PM) metabolizers of mephenytoin. The frequencies of PMs for mephenytoin and debrisoquine hydroxylation activity were 2.6% and 7.0%. These two defects in oxidative metabolism were not observed in the same subjects, which suggests that 4-hydroxylation of mephenytoin is a new polymorphism independent of that for debrisoquine.

Administration, Oral↗
PubMed1984

Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.

To assess the relative contributions of encainide and its putatively active metabolites, O-demethyl encainide (ODE) and 3 methoxy-O-demethyl encainide (3MODE), to the drug's pharmacologic effects, we compared intravenous infusions and sustained oral therapy in two phenotypically distinct groups of patients, extensive and poor metabolizers of encainide. Unlike poor metabolizers, extensive metabolizers had appreciable quantities of both metabolites detectable in plasma and had fourfold shorter elimination half-lives for encainide. By quantitating electrocardiogram intervals, arrhythmia frequency, and plasma concentrations, we found that, in poor metabolizers, arrhythmia suppression and ventricular complex (QRS) prolongation were correlated positively with encainide concentrations (r greater than or equal to 0.570, P less than 0.014). In these two subjects, antiarrhythmic concentrations of encainide (greater than 265 ng/ml) were at least fivefold higher than those sustained in the six extensive metabolizers during steady state oral therapy. In extensive metabolizers, encainide concentrations were uncorrelated with effects. Arrhythmia suppression and QRS prolongation in extensive metabolizers correlated best with ODE (r greater than or equal to 0.816, P less than 0.001); QTc change correlated positively with both 3MODE and ODE. Arrhythmia suppression paralleled QRS prolongation; the relationship between them appeared similar in both phenotypic groups. In most patients, extensive metabolizers, encainide effects during oral therapy are mediated by metabolites, probably ODE.

Aged↗
PubMed1984

A new method for constant plasma drug concentrations: application to lidocaine.

Optimal intravenous drug therapy often requires the rapid achievement and maintenance of therapeutic plasma drug concentrations. Simple regimens (single bolus and maintenance infusion) can produce wide variations in plasma drug concentrations early in therapy, and more complex regimens require a series of precisely timed infusion rate changes to minimize such variability. A new simple method of delivering an infusion produces a delivery rate that declines exponentially, thereby providing stable plasma concentrations after a bolus dose. The method requires no specialized equipment and no intervention once started. The method has been tested both ex vivo and in normal volunteers receiving lidocaine. Stable lidocaine plasma concentrations are rapidly achieved and maintained within the therapeutic range. Further evaluation of this approach in patients is indicated.

Humans↗
PubMed1984

Influence of genetic polymorphism on the metabolism and disposition of encainide in man.

The metabolism of the new, highly effective antiarrhythmic agent, encainide, appears to be polymorphically distributed in a similar fashion to the genetically determined oxidative biotransformation of debrisoquine. Accordingly, the disposition of encainide and known metabolites was investigated after simultaneous acute i.v. (radiolabeled) and single and multiple oral (nonradiolabeled) dosing to two groups of normal subjects characterized as "poor" (PM) and "extensive" (EM) metabolizers of debrisoquine. Pronounced differences in both the plasma concentration/time curves and the 24-hr urinary excretion of encainide and metabolites were observed between the two phenotypes. In the EM group, the oral bioavailability of encainide was only about 25 to 30% because of extensive presystemic (first-pass) metabolism, and no accumulation occurred after multiple oral dosing with 50 mg every 8 hr for 3 days, as the elimination half-life of the drug was about 2.5 hr. The major metabolite formed was O-desmethylencainide which accounted for almost half of the identified urinary metabolites and represented about 10% of the administered dose. This metabolite was present in 5- to 10-fold higher concentrations in the plasma than unchanged drug and accumulated almost 2-fold after multiple oral dosing. 3-Methoxy-O-desmethylencainide also was present at higher concentrations than encainide and accumulated on multiple dosing similarly to O-desmethylencainide. N,O-didesmethylencainide was a minor metabolite only detectable in the urine and N-desmethylencainide was not measurable in either plasma or urine. In contrast, in the PM group, encainide plasma concentrations were 10- to 20-fold higher than in the EMs after both oral and i.v. administration and the elimination half-life was 3- to 4-fold longer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗