The effect of chronic (greater than 3 months) administration of low-dose oestrogen-containing (less than 50 micrograms oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.7501/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 micrograms/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.

Studies in rats indicate that the metabolic activation of acetylhydrazine, a metabolite of isoniazid, is a critical determinant of the hepatotoxicity of isoniazid. As demonstrated in that model, the formation of 14CO2 after the administration of 14C-acetylisoniazid reflects the activity of the toxic pathway. A similar approach in man should make it possible to demonstrate the presence and to assess the quantitative importance of this toxifying pathway, and thus to evaluate its role in the pathogenesis of isoniazid hepatitis. We gave 300 mg isoniazid together with 10 microCi 14C-acetylisoniazid (12 mg) to 17 healthy subjects and determined the time course of the plasma concentrations of isoniazid, acetylisoniazid, acetylhydrazine, and diacetylhydrazine and of the exhalation of 14CO2. The time course of 14CO2 in breath closely paralleled the plasma concentration-time curve of acetylhydrazine but not those of acetylisoniazid or diacetylhydrazine, indicating that the 14CO2 originated directly from the metabolism of acetylhydrazine. The cumulative exhalation of 14CO2 increased with decreasing rate of acetylation of isoniazid, such that slow acetylators generated more 14CO2 than rapid acetylators. Simulation studies demonstrated that even if the data are corrected for the different formation of acetylisoniazid from isoniazid in slow and rapid acetylators, the slow acetylators still generated more 14CO2. The data therefore indicate that a substantial fraction of the acetylhydrazine formed from isoniazid passes through a pathway that has been shown in animals to generate highly reactive and hepatotoxic intermediates.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied verapamil pharmacodynamics and disposition in seven young, ten elderly, and seven very elderly hypertensive males. Maximal decrease in mean (+/- SD) blood pressure tended to be greater in the elderly (-13.5 +/- 5.9 mm Hg) and the very elderly patients (-15.9 +/- 9.6 mm Hg) compared with that in young patients (-7.3 +/- 4.2 mm Hg). Disparate effects on heart rate responses were noted with reflex tachycardia in young patients compared with decreases in heart rate among the elderly and very elderly. Sensitivity to verapamil-induced prolongation in electrocardiographic P-R interval was less in the very elderly, and maximal prolongation in P-R interval induced by verapamil was less in the elderly and very elderly. Verapamil disposition was also age related. Total verapamil clearance was decreased in elderly (10.5 +/- 3.5 mL/min X kg; p less than 0.05) and very elderly (8.0 +/- 4.1 mL/min X kg; p less than 0.01) when compared with that in young patients (15.5 +/- 4.5 mL/min X kg). Elimination half-life was prolonged in the elderly (7.4 +/- 3.3 h; p less than 0.01) and very elderly (8.0 +/- 1.2 h; p less than 0.01) compared with that in young patients (3.8 +/- 1.1 h). Our data indicate age- and hypertension-related physiologic changes result in predictable pharmacokinetic changes. However, the complex alterations in verapamil pharmacodynamic responses indicate an interaction between direct drug effects and age- and disease-related changes in hemodynamic and autonomic nervous system function.

Abstract-Lipoprotein(a) [Lp(a)] is a novel risk factor for atherosclerosis, whose role in multiracial populations has been debated. We recently demonstrated a significant association of elevated levels of Lp(a) [1][2][3][4][5][6][7] and in most prospective studies. 8 -13 No significant associations between Lp(a) levels and CAD have been found in African Americans, although Lp(a) levels are higher than the levels in whites. 14,15 This lack of association has resulted in uncertainty regarding the role of Lp(a) as a risk factor for atherosclerosis. Furthermore, there is a paucity of data on associations between Lp(a) and CAD in Hispanics.The apo(a) locus determines Ϸ90% of the variation in plasma Lp(a) levels. 16 The apo(a) gene contains a variable number of copies of the kringle 4 (K4) domain, resulting in an apo(a) protein size polymorphism. 17 There is a general inverse relationship between apo(a) size and Lp(a) levels. 18 Whether the higher Lp(a) levels in African Americans can be attributed to genetic differences in apo(a) has not been clarified. 19 The complexity of this issue is illustrated by a recent study concluding that Lp(a) levels, primarily those in the intermediate apo(a) isoform size range (20 to 25 K4 repeats), were greater among African Americans than whites. 20 The size polymorphism of apo(a) has been suggested to be of importance in conveying risk for cardiovascular disease, inasmuch as several studies (largely carried out in white populations) have shown an association between small apo(a) isoform sizes and CAD or cerebrovascular disease. [21][22][23][24][25][26] Indeed, in some of these studies, high plasma Lp(a) levels were associated with CAD only among carriers of small apo(a) isoform sizes. 23,25,26 In a recent case-control study, we demonstrated that elevated levels of Lp(a) associated with small apo(a) size was a risk factor for CAD in African American and white men. 27 We concluded that the difference in distribution of Lp(a) levels over specific apo(a) sizes between African Americans and whites likely had confounded previous results. Interestingly, no significant association was found in women, irrespective of ethnicity. To confirm these findings on a population level and to extend them to cardiovascular disease beyond CAD, we evaluated the relationship between Lp(a) levels, apo(a) isoform size, and carotid atherosclerosis in a random sample from an elderly multiethnic population.

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