Frequency distribution of dapsone N-hydroxylase, a putative probe for P4503A4 activity, in a white population

May, Danica; Porter, James A.; Wilkinson, Grant R.; Branch, Robert A.

doi:10.1038/clpt.1994.62

Cited by 89 publications

(47 citation statements)

References 4 publications

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“…However, the results obtained in our study did not show a significant difference in non-stereoselective pharmacokinetic parameters of T and M1 between the two genders in our volunteers. This finding is in concordance with the results of the study of May et al that debrisoquine 4-hydroxylation is not influenced by gender [15].…”

Section: Discussionsupporting

confidence: 95%

Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers

Ardakani¹,

Rouini²

2007

Biopharm & Drug Disp

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By using a high-performance liquid chromatography method, the pharmacokinetics of the tramadol (T) and its three main metabolites, O-desmethyltramadol (M1), N-desmethyltramadol (M2) and O,N-didesmethyltramadol (M5) was studied in healthy male and female Iranian volunteers after oral administration of two 50 mg tramadol hydrochloride tablets. The related pharmacokinetic parameters such as C(max), T(max), AUC((0-t)), AUC((0-infinity)), T(1/2) and Cl/F were calculated and compared between the two genders. No significant differences were found in the systemic exposure and pharmacokinetic of tramadol, M1 and M2 while there were significant differences in AUCs of M5 in the two genders. It was concluded that to get a more accurate result, the gender dependency of T and its metabolites might be studied in specific phenotypes.

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Section: Discussionsupporting

confidence: 95%

Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers

Ardakani¹,

Rouini²

2007

Biopharm & Drug Disp

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“…Recently, it has been shown that weight-normalized CL due to oxidative metabolism is negatively correlated with age (7), while conjugative metabolism does not correlate. This is in agreement with our observation, because oral CL of dapsone is associated with CL formation of the N-hydroxyl metabolite but is independent of the acetylation process (10). Lower protein binding in smaller children may partially account for the higher CL, because dapsone is a low-extractionratio drug.…”

Section: Discussionsupporting

confidence: 82%

Pharmacokinetics of dapsone in human immunodeficiency virus-infected children

Gatti

Loy

Casazza

et al. 1995

Antimicrob Agents Chemother

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Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means ؎ standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 ؎ 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 ؎ 1.3 (2 to 6) h; half-life at elimination phase, 24.2 ؎ 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 ؎ 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 ؎ 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r ‫؍‬ 0.614 and P ‫؍‬ 0.034), as did V (r ‫؍‬ 0.631 and P ‫؍‬ 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r ‫؍‬ 0.765 and P ‫؍‬ 0.004, and for V/F to height, r ‫؍‬ 0.748 and P ‫؍‬ 0.005). Since oral CL from plasma and V were positively and highly correlated (r ‫؍‬ 0.898 and P ‫؍‬ 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.

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“…Phenotyping in healthy populations has both found and failed to find gender differences. 68,75,76 For propranolol, sex differences have been shown in Caucasians 47,77 and in Chinese volunteers with lower clearance in women compared with men. 78 Limited data regarding sex differences are available from clinical populations receiving CYP2D6 substrates.…”

Section: Phase I Metabolism (Oxidation Reduction and Hydrolysis)mentioning

confidence: 96%

Gender-Specific Implications for Cardiovascular Medication Use in the Elderly

Schwartz

2003

Cardiology in Review

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Sex should be considered during the selection of cardiovascular medications and dosages of cardiovascular medications. There is mounting evidence that clinically important differences between the sexes exist in the pharmacokinetic processes that determine drug concentrations and in the pharmacodynamic processes that determine physiologic responses to pharmacologic agents. Although aging also affects these processes, aging does not eliminate the sex-related differences. The major pharmacokinetic differences between the sexes, on average, are lower weight and distribution volumes in women compared with men and lower renal drug clearance in women compared with men. Sex-related differences in hepatic drug clearance are less predictable. Pharmacodynamic responses that differ between the sexes include increased adverse cardiovascular drug effects in women compared with men (torsade de pointes arrhythmias, increased risk of hemorrhagic consequences of anticoagulation or thrombolytic therapy, electrolyte abnormalities with diuretics, myopathy with HMG Co-A reductase inhibitors, cough with ACE inhibitors, and increased incidence of thrombosis). Recommendations for optimizing cardiovascular drug therapy for the older women include individualization of drug selection to minimize the number of medications and side effects; dosage adjustment based on age, size, and sex; close monitoring for side effects; and consideration of cost and access to medications. Optimal care for the older woman with cardiovascular disease will also require investigation of cardiovascular medications in older women and of therapies for cardiovascular diseases that are more common in women than men.A lthough there is increasing evidence to support invasive and acute cardiac interventions in the elderly, most of therapeutic cardiac interventions for the elderly are pharmacologic. It is therefore important to periodically review evolving clinical concepts for drug selection and modifications for patient subgroups. Despite the underrepresentation of women in clinical investigations and cardiovascular clinical trials, 1-3 it is becoming clear that the response to medications may differ between the sexes. One striking example of the impact of sex differences in drug responses is highlighted by drug withdrawals from the US market during the period from 1997 until early 2001. Of the 10 drugs removed from marketing during that period, 4 were prescribed more frequently to women (for weight loss [dexfenfluramine as Redux and dexfenfluramine as Pondimin], for diabetes [troglitazone as Rezulin], and for inflammatory disease (Lotronex)] and 4 had higher rates of toxicity in women but were prescribed in equal rates to men and women (for hypertension [Mibefradil as Posicor] antihistamines [terfenadine as Seldane or Hismanal], heartburn [cisapride as Propulsid]. Two were prescribed in equal rates and had equal toxicity in men and women (grepafloxacin, an oral fluroquinolone antibiotic, as Raxar; and for pain relief, bromfenac as Duract). In later 2001, cerivastatin...

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Frequency distribution of dapsone N-hydroxylase, a putative probe for P4503A4 activity, in a white population

Cited by 89 publications

References 4 publications

Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers

Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers

Pharmacokinetics of dapsone in human immunodeficiency virus-infected children

Gender-Specific Implications for Cardiovascular Medication Use in the Elderly

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