Differences In Metabolic Clearance Research Articles

Correction to "Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers".

Correction to "Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers".

Individual Differences in Metabolic Clearance of S-Warfarin Efficiently Mediated by Polymorphic Marmoset Cytochrome P450 2C19 in Livers.

Marmoset cytochrome P450 2C19, highly homologous to human P450 2C9 and 2C19, has been identified in common marmosets (Callithrix jacchus), a nonhuman primate species used in drug metabolism studies. Although genetic variants in human and macaque P450 2C genes account for the interindividual variability in drug metabolism, genetic variants have not been investigated in the marmoset P450 2C19 In this study, sequencing of P450 2C19 in 24 marmosets identified three variants p.[(Phe7Leu; Ser254Leu; Ile469Thr)], which showed substantially reduced metabolic capacity of S-warfarin compared with the wild-type group in vivo and in vitro. Although mean plasma concentrations of R-warfarin in marmosets determined after chiral separation were similar between the homozygous mutant and wild-type groups up to 24 hours after the intravenous and oral administrations of racemic warfarin, S-warfarin depletion from plasma was significantly faster in the three wild-type marmosets compared with the three homozygous mutant marmosets. These variants, cosegregating in the marmosets analyzed, influenced metabolic activities in 18 marmoset liver microsomes because the homozygotes and heterozygotes showed significantly reduced catalytic activities in liver microsomes toward S-warfarin 7-hydroxylation compared with the wild-type group. Kinetic analysis for S-warfarin 7-hydroxylation indicated that the recombinant P450 2C19 Ser254Leu variant would change the metabolic capacity. These results indicated that the interindividual variability of P450 2C-dependent drug metabolism such as S-warfarin clearance is at least partly accounted for by P450 2C19 variants in marmosets, suggesting that polymorphic P450 2C-dependent catalytic functions are relatively similar between marmosets and humans.

Individual differences in in vitro and in vivo metabolic clearances of antipsychotic risperidone from Japanese subjects genotyped for cytochrome P450 2D6 and 3A5.

There are conflicting reports regarding the effects of cytochrome P450 (P450, CYP) genotypes on the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone (paliperidone), in clinical patients. The aim of this study was to investigate individual differences in the metabolic clearance of risperidone in vitro and in vivo. In vitro liver microsomal risperidone 9-hydroxylation activities and in vivo plasma concentrations of risperidone and paliperidone were investigated in 15 male and 12 female Japanese subjects (mean age 52 years, range: 24-75 years) genotyped for CYP2D6 and CYP3A5. CYP2D6 intermediate and poor metabolizers showed significantly lower liver microsomal risperidone 9-hydroxylation activities than extensive metabolizers did at 5 μM of risperidone; this difference was not evident at 50 μM of risperidone. The recombinant CYP3A5 Vmax/Km value for risperidone 9-hydroxylation was 30% that of CYP3A4, and liver microsomes from CYP3A5 expressers had similar risperidone 9-hydroxylation activities to those of CYP3A5 poor expressers. The plasma concentration/dose ratios for risperidone and paliperidone in 27 Japanese patients were not significantly influenced by the CYP2D6 or CYP3A5 genotypes. Individual differences in metabolic clearance of risperidone under the present conditions were not significantly influenced by the genotypes of CYP2D6 or CYP3A5.

Lower metabolic clearance of tizanidine in Japanese subjects

Our aim was to determine whether metabolic clearance, renal clearance, or both elimination pathways contribute to ethnic differences in tizanidine clearance, which is ~ 2-fold higher in Caucasians than in Asians. The pharmacokinetic parameters of tizanidine in 9 healthy male Japanese subjects were compared with those of Caucasians in previous studies. Metabolic clearance of tizanidine was lower in Japanese than in Caucasian subjects (5.9 vs. 8.1 - 10.9 l/h/kg), although renal clearances were similar (0.040 vs. 0.047 - 0.055 l/h/kg). The results suggest that ethnic differences in tizanidine clearance are due to differences in metabolic clearance.

Circulating non-22 kDa growth hormone isoforms after a repeated GHRH stimulus in normal subjects

The aim of this study was to evaluate the proportion of non-22 kDa GH isoforms in relation to total GH concentration after a repeated GHRH stimulus in healthy subjects. We studied 25 normal volunteers (12 males and 13 females, mean age 13.1 years, range 6–35), who received two GHRH bolus (1.5 μg/kg body weight, i.v.) administered separately by an interval of 120 minutes. The proportion of non-22 kDa GH was determined by the 22 kDa GH exclusion assay (GHEA), which is based on immunomagnetic extraction of monomeric and dimeric 22 kDa GH from serum, and quantitation of non-22 kDa GH isoforms using a polyclonal GH assay. Samples were collected at baseline and at 15–30 min intervals up to 240 min for total GH concentration. Non-22 kDa GH isoforms were measured in samples where peak GH after GHRH was observed. Total GH peaked after the first GHRH bolus in all subjects (median 37.2 ng/ml; range: 10.4–94.6). According to GH response to the second GHRH stimulus, the study group was divided in “non-responders” ( n = 7; 28%), with GH peak levels lower than 10 ng/ml (median GH: 8.7 ng/ml; range 7.3–9.6) and “responders” ( n = 18; 72%), who showed a GH response greater than 10 ng/ml (median 17 ng/ml; range 10.1–47.0). The median proportion of non-22 kDa GH on the peak of GH secretion after the first GHRH administration was similar in both groups (“responders” median: 8.6%, range 7–10.9%; “non-responders” median: 8.7%, range 6.7–10.3%), independently of the type of response after the second GHRH. In contrast, the median proportion of non-22 kDa GH was greater at time of GH peak after the second GHRH bolus in the “non-responders” (median 11.4%; range 9.1–14.3%) in comparison with the “responders” (median 9.1%; range 6.7–11.9%; p = 0.003). A significant negative correlation between the total GH secreted and the percentage of non-22 kDa isoforms was seen in the “non-responders” ( p = 0.003). These differences in GH response to repeated GHRH stimulation and in the pattern of GH isoforms at GH peak among subjects might be due to distinct recovery patterns of somatrotrophic function and/or differences in metabolic clearance of GH isoforms.

Meal-induced 24-hour profile of circulating glycated insulin in type 2 diabetic subjects measured by a novel radioimmunoassay

Increasing evidence supports a role for glycated insulin in the insulin-resistant state of type 2 diabetes. We measured 24-hour profiles of plasma glycated insulin, using a novel radioimmunoassay (RIA), to evaluate the effects of meal stimulation and intermittent fasting on circulating concentrations of plasma glycated insulin in type 2 diabetes. Patients (n = 6; hemoglobin A1c [HbA1c], 7.2% ± 0.6%; fasting plasma glucose, 7.4 ± 0.7 mmol/L; body mass index [BMI], 35.7 ± 3.5 kg/m2; age, 56.3 ± 4.4 years) were admitted for 24 hours and received a standardized meal regimen. Half-hourly venous samples were taken for plasma glycated insulin, glucose, insulin, and C-peptide concentrations between 8 am and midnight and 2-hourly overnight. The mean plasma glycated insulin concentration over 24 hours was 27.8 ± 1.2 pmol/L with a mean ratio of insulin:glycated insulin of 11:1. Circulating glucose, insulin, C-peptide, and glycated insulin followed a basal and meal-related pattern with most prominent increments following breakfast, lunch, and evening meal, respectively. The mean concentrations of glycated insulin during the morning, afternoon, evening, and night-time periods were 24.4 ± 2.5, 28.7 ± 2.3, 31.1 ± 2.1, and 26.2 ± 1.5 pmol/L, respectively, giving significantly higher molar ratios of insulin:glycated insulin of 18.0:1, 14.2:1, and 12.7:1 compared with 7.0:1 at night (P <.01 to P <.001). These data demonstrate that glycated insulin circulates at relatively high concentrations in type 2 diabetes with a diurnal pattern of basal and meal-stimulated release. A higher proportion of glycated insulin circulates at night suggestive of differences in metabolic clearance compared with native insulin. © 2003 Elsevier Inc. All rights reserved.

Pharmacokinetics and efficacy of structurally related spirohydantoin and spirosuccinimide aldose reductase inhibitors.

1. Six potent aldose reductase inhibitors (ARI), three spirohydantoin (I to III) and three spirosuccinimide (IV to VI) compounds, showed similar IC50 activities in vitro for the inhibition of rat lens aldose reductase, but their ED50 values in diabetic rats varied as much as 20-fold in the lens and 50-fold in the sciatic nerve tissue. Pharmacokinetic studies were undertaken to investigate these findings. Structure-pharmacokinetic relationships were studied following i.v. administration to cynomolgus monkeys. 2. The clearance (CL) of each spirosuccinimide ARI was faster (greater than 5 times) than that of the corresponding spirohydantoin compound. In both series the CL values of the C(4) methyl and methoxy analogues were 4-fold greater than those for the unsubstituted compounds, although the CL values of the methoxy and methyl derivatives in the same series were not significantly different. 3. The volumes of distribution (Vss) of the spirohydantoins were about one-half those of the corresponding spirosuccinimides, and the Vss values of the parent compounds of both ARI series did not differ dramatically from those of their methyl and methoxy analogues. 4. All six compounds were eliminated from plasma in a biexponential fashion. The half-lives (lambda 1 and lambda 2) of the spirohydantoin compounds were much longer than those of the corresponding spirosuccinimide compounds, and the unsubstituted compounds had longer half-lives than their methyl and methoxy derivatives. The longest lambda 1 and lambda 2 half-lives were observed for imirestat, while two of the spirosuccinimides had the shortest half-lives. 5. These results indicate that the relationships observed between the in vitro and in vivo activities of the six ARI can be attributed to structurally dependent differences in metabolic clearance.

Pharmacokinetics of ticlopidine during chronic oral administration to healthy volunteers and its effects on antipyrine pharmacokinetics.

1. The pharmacokinetics of ticlopidine, a novel antithrombotic agent, have been investigated in 10 healthy volunteers dosed orally with the drug (250 mg 12 hourly for 21 days), to determine the basic pharmacokinetic parameters in humans, to investigate its accumulation during repeated administration, and to assess its effects on hepatic drug-metabolizing enzymes. 2. After the first dose, peak plasma concentrations (median 0.31, range 0.08-0.80 mg/l) were generally found at 2 h. The levels decreased rapidly to a median concentration of 0.087 mg/l by 4 h then declined to 0.022 (range less than 0.005-0.128) mg/l at 12 h after administration, with apparent half-lives of approx. 4 h. The median AUC value for this first dosage interval (AUC tau) was 0.97 (range 0.41-3.49) mg h l-1. 3. Pre-dose plasma concentrations indicated that steady state was reached after 5-10 days, and then remained essentially unchanged through to the end of the study. From 30 h after the final dose, drug levels declined exponentially with a median half-life of 28.8 (range less than or equal to 20-50) h. 4. Following the final dose, the median peak concentration and AUC tau were 0.99 (range 0.22-2.12) mg/l and 4.06 (range 0.90-15.2) mg h l-1 respectively. Based on AUC values, the mean accumulation factor +/- SD was 3.73 +/- 1.14. 5. The metabolic status of subjects was assessed by administration of single doses of antipyrine (700 mg orally) 7 days before the first dose of ticlopidine and 2 days after the final dose. Treatment with ticlopidine decreased antipyrine clearance, demonstrating that it inhibited drug-metabolizing enzymes. Significant correlations (r2 = 0.84, p less than 0.01) were found between the AUC values for ticlopidine and antipyrine, indicating that the interindividual variation in the pharmacokinetics of ticlopidine are explained by differences in metabolic clearance.

Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH

The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml.min-1; S 379 ml.min-1) than in EMs (R 783 ml.min-1; S 828 ml.min-1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml.min-1; S 201 ml.min-1) relative to extensive metabolisers (R 533 ml.min-1; S 586 ml.min-1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml.min-1) than extensive (267 ml.min-1) metabolisers. The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng.ml-1 would not be attained in the PMs studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular responsiveness to norepinephrine in mild essential hypertension

The responses of blood pressure, heart rate and forearm vascular resistance to exogenous norepinephrine (NE) were measured in 40 normotensive and 65 mildly hypertensive subjects (mean blood pressure 117/72 and 146/92 mm Hg, respectively). Both groups received low incremental doses of NE: 15, 30 and 60 ng/kg/min for 8 minutes each. In contrast to previous studies that compared the dose-response curves in normo- and hypertensive subjects, this study corrected the cardiovascular responses for the increment of plasma NE to account for differences in metabolic clearance of NE. Although age and sex appeared to play a role, the corrected cardiovascular responses did not differ significantly between normo- and hypertensive subjects. Thus, an increased cardiovascular sensitivity to exogenous NE was not demonstrated in mildly hypertensive subjects. This finding confirms some but not all previous studies of the dose-response relation.

Structure‐activity relationships of species‐selectivity in acute chemical toxicity between fish and rodents

AbstractAlthough regression analyses between the acute oral or intraperitoneal LD50 values for both rats (Rattus norvegicus) and mice (Mus musculus) and the 96‐h LC50 values for fathead minnows (Pimephales promelas) or rainbow trout (Salmo gairdneri) for a broad spectrum of environmental chemicals were statistically significant, the large variability in the regressions limits their practical utility for interspecies extrapolations. To gain a better understanding of this variability, analyses were performed to reveal the structural features characteristic of those chemicals that deviate substantially from the interspecies regressions. The criterion selected to indicate excessive variability was a greater‐than‐fourfold difference between the observed rodent LD50 and that estimated from the regression against the fish data. Discriminant function analyses showed aldehydes, esters and organophosphorus insecticides to be the primary outliers in the fish‐to‐rodent comparisons. Rodents were generally less sensitive to intoxication with carbonyl‐containing compounds but more sensitive to organophosphate anticholinesterase poisoning than were fish. This species‐selectivity for both classes of chemicals correlates with species‐related differences in metabolic clearance and/or pharmacodynamic differences in target organ sensitivities. Since these same idiosyncracies in metabolic disposition and receptor sensitivity would be suspected to be operative for structurally related chemical compounds, interspecies extrapolations of toxicity information for both carbonyl compounds and for anticholinesterase agents should take into consideration these important factors, which confer certain degrees of species‐selectivity for these chemical classes.

STRUCTURE-ACTIVITY RELATIONSHIPS OF SPECIES-SELECTIVITY IN ACUTE CHEMICAL TOXICITY BETWEEN FISH AND RODENTS

Although regression analyses between the acute oral or intraperitoneal LD50 values for both rats (Rattus norvegicus) and mice (Mus musculus) and the 96-h LC50 values for fathead minnows (Pimephales promelas) or rainbow trout (Salmo gairdneri) for a broad spectrum of environmental chemicals were statistically significant, the large variability in the regressions limits their practical utility for interspecies extrapolations. To gain a better understanding of this variability, analyses were performed to reveal the structural features characteristic of those chemicals that deviate substantially from the interspecies regressions. The criterion selected to indicate excessive variability was a greater-than-fourfold difference between the observed rodent LD50 and that estimated from the regression against the fish data. Discriminant function analyses showed aldehydes, esters and organophosphorus insecticides to be the primary outliers in the fish-to-rodent comparisons. Rodents were generally less sensitive to intoxication with carbonyl-containing compounds but more sensitive to organophosphate anticholinesterase poisoning than were fish. This species-selectivity for both classes of chemicals correlates with species-related differences in metabolic clearance and/or pharmacodynamic differences in target organ sensitivities. Since these same idiosyncracies in metabolic disposition and receptor sensitivity would be suspected to be operative for structurally related chemical compounds, interspecies extrapolations of toxicity information for both carbonyl compounds and for anticholinesterase agents should take into consideration these important factors, which confer certain degrees of species-selectivity for these chemical classes.

Metabolic clearance rates of isohormones of human growth hormone in man.

The charge isomers of human GH (/GH), isohormones C, D, and E, which result from limited proteolytic cleavage exhibit enhanced biological activity in the rat and in man compared to the intact polypeptide and most abundant form, isohormone B. The mechanism leading to enhanced activity is unknown. To examine the possibility that different in vivo metabolism may represent one such mechanism, the MCRs of radioiodinated hGH-B, -C, and -D were measured in seven normal adults. Significant differences in metabolic clearance were found between isohormones (hGH-B, 108.4; hGH-C, 67.9; hGH-D, 55.7 liters/m2-day). It is concluded that in man, the enzymatically cleaved hGH isohormones are cleared more slowly than hGH-B. Slower metabolism may be a factor responsible for the enhanced biological activity of proteolytically cleaved hGH isohormones.