Effect of Age and Gender on Pharmacokinetics of Atorvastatin in Humans

Gibson, Donald M.; Bron, Nicola J.; Richens, A.; Hounslow, Neil; Sedman, Allen J.; Whitfield, Lloyd R.

doi:10.1002/j.1552-4604.1996.tb04194.x

Cited by 84 publications

(45 citation statements)

References 11 publications

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“…Moreover, the importance of sex was often overlooked by using only the ''preferred'' sex in pharmacotoxicological studies, the male rat, or worse yet, not even recording the sex of the animal. Nevertheless, in agreement with limited human findings (4,(7)(8)(9), rodent studies observed an aging-and sex-related decline in the in vivo and in vitro metabolism of different classes of drugs and subnormal baseline concentrations of various components of the hepatic drugmetabolizing enzyme system (10)(11)(12). With the identification in the 1980s of the multiple isoforms of P450 (designated with the initial letters CYP) it became apparent that males were more susceptible to aging-induced declines in drug metabolism than were females.…”

supporting

confidence: 89%

Interpulse growth hormone secretion in the episodic plasma profile causes the sex reversal of cytochrome P450s in senescent male rats

Dhir

Shapiro

2003

Proc. Natl. Acad. Sci. U.S.A.

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Humans as well as other mammals experience an aging-related decline in drug metabolism as well as a diminution in growth hormone secretion. In the case of rats, these events are more pronounced in senescent males, whose expression of male-specific isoforms of cytochrome P450, the major drug-metabolizing enzymes and constituting Ϸ60 -70% of the total cytochrome P450 in male rat liver, is completely suppressed, whereas female-dependent isoforms are remarkably induced to female-like levels. Overlooked in these independently reported studies is the fact that ''signals'' inherent in the masculine episodic and female continuous growth hormone profiles regulate expression and͞or suppression of the dozen or so sex-dependent cytochrome P450 isoforms in rat liver. Whereas previous studies identified profound reductions in the pulse amplitudes of the masculine growth hormone profile as the cause for the diminished hormone secretion during aging, pulse heights are not recognized by the cytochromes as regulatory signals. Instead, we have shown that just a nominal secretion of growth hormone during the usual growth hormone-devoid interpulse period in the masculine episodic profile can explain the complete repression of male-specific CYP2C11, CYP3A2, and CYP2A2 and induction of female-dependent CYP2C12, CYP2C6, and CYP2A1 observed in senescent male rats. T wo presumably unrelated aging-induced events were first identified in humans: a decline in drug-metabolizing capacity and a reduction in growth hormone secretion. Regarding the former, it is commonly known that the elderly experience abnormally high incidences of adverse drug reactions and toxicities (1, 2), resulting, at least in part, from a decline in drug-metabolizing enzymes (3) and requiring that doses of therapeutic drugs often be reduced in older patients (4). Concerning the latter, an aging-induced reduction in growth hormone secretion is well characterized, secretion declining by Ϸ14% per decade from late puberty as a result of continuously decreasing pulse amplitudes (5, 6). Unfortunately, direct studies on liver drug metabolism and growth hormone regulation in elderly people are scant, and most evidence is derived from animal studies.Although animal research has been much more thorough and invasive than studies conducted in humans, results with animals have been surprisingly consistent with findings from humans. Early investigations using laboratory animals had to limit their analyses to nonspecific drug-metabolizing enzymes whose activities are dependent on the contributions of multiple isoforms of cytochrome P450 (P450). Moreover, the importance of sex was often overlooked by using only the ''preferred'' sex in pharmacotoxicological studies, the male rat, or worse yet, not even recording the sex of the animal. Nevertheless, in agreement with limited human findings (4, 7-9), rodent studies observed an aging-and sex-related decline in the in vivo and in vitro metabolism of different classes of drugs and subnormal baseline concentrations of various components of t...

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supporting

confidence: 89%

Interpulse growth hormone secretion in the episodic plasma profile causes the sex reversal of cytochrome P450s in senescent male rats

Dhir

Shapiro

2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Atorvastatin has a long half-life (approximately 14 hours) allowing its administration at any time of day [6], with active metabolites effective for 20-30 hours [5,6]. This makes it an ideal candidate for alternate-day dosing [7,8]. In addition to many helpful effects of statins, they are among the more expensive drugs.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of alternate day dosing of atorvastatin

Aghasadeghi

Zare

2008

Open Medicine

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AbstractAtorvastatin is a synthetic inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. It has a longer half life and longer duration of action than that of all other available HMG-CoA inhibitors. We evaluated the efficacy of alternate-day dosing of atorvastatin in comparison with the standard one-daily dose on total cholesterol, low and High-density lipoprotein (LDL and HDL) and triglycerides. This study is a randomized, blinded, and controlled clinical trial. Sixty-six patients with LDL cholesterol of more than 100 mg/dl were enrolled. Baseline fasting lipid profile (total cholesterol, LDL, HDL and triglyceride), liver function tests and creatine kinase were drawn. Patients were randomized to three atorvastatin dose groups. Group I received 10 mg of atorvastatin every day, group II received 20 mg of atorvastatin every day, and group III received 20 mg every other day. After 6 weeks of treatment with atorvastatin, fasting lipid profiles, liver function tests and creatine kinase concentrations were re-taken. Compliance to treatment was assessed at each visit. Of the sixty-six patients enrolled, sixty completed the study. All three regimens significantly reduced total cholesterol and LDL compared to baseline. No statistically significant difference existed between the three groups in regards to total or a percentage decrease in total cholesterol and LDL cholesterol at 6 weeks compared to baseline. All regimens were well tolerated and none of the patients showed significant elevation of liver enzyme or creatine kinase during the course of the study. In conclusions the alternate-day dosing of atorvastatin is an efficacious and safe alternate to daily dosing and yet inexpensive.

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“…Females tend to have a higher percentage of body fat, which affects the volume of distribution of some drugs and can significantly increase the half-life of a variety of medications, including the more lipophilic statins [16]. A study investigated the effects of sex/gender on the pharmacokinetics of Atorvastatin after administration of 20 mg tablets [39]. The equivalent maximum concentration (Cmax) of Atorvastatin was 17.6% higher in women than in men.…”

Section: Sex/gender Disparities In Statin Utilization From Clinical Pmentioning

confidence: 99%

“…The equivalent maximum concentration (Cmax) of Atorvastatin was 17.6% higher in women than in men. In addition, the mean area under the concentration-time curve (AUC0-infinity) and half-life (t1/2) were 11.3% lower and 19.9% shorter, respectively, in women than in men [39]. In a Chinese study, a pharmacokinetics study was conducted on 12 volunteers following a single dose of 1 mg, 2 mg and 4 mg of Pitavastatin [40].…”

Section: Sex/gender Disparities In Statin Utilization From Clinical Pmentioning

confidence: 99%

Sex/Gender -Based Pharmacology and Statin Utilization Amongst Elderly Patients with Diabetes

Farahani

Johnson²,

Whitehead³

et al. 2015

CIM

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Purpose: The purpose of this study was to explore the ten-year trends in utilization of bioequivalent doses of statin amongst elderly patients with diabetes according to sex/ gender in Ontario, Canada. Methods:A cohort of patients with diabetes (>65 years) was constructed using the Ontario Diabetes Database Statin utilization data (2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012) was obtained from the Ontario Drug Benefit Program for both women and men. Bioequivalent doses for statins were calculated according to the dosing conversion factor in therapeutic interchange programs in clinical practice. Utilization pattern of high potency (Atorvastatin and Rosuvastatin) vs. low potency statins (Simvastatin, Lovastatin, Fluvastatin, Pravastatin) were also analyzed. Results:The average bioequivalent Simvastatin utilization in 2003 was 29.22 mg/day for women and 30.35 mg/day for men. By 2008, this gap in dosing was higher for both women and men and by 2013 it had increased to 47.75 mg/day for women and 52.98 mg/day for men. For average number of day supply per year, there was no significant trend of changes over the 10-year period, although the use of high potency statins increased significantly (P<0.001) for both women and men. No differences were seen for sex/gender; either for the 10-year period or for each year.Conclusions: There has been significant increase in bioequivalent statin utilization amongst elderly patients with diabetes in Ontario; for both men and women. In a publiclyfunded healthcare system such as Ontario, there were no sex/gender differences in the utilization of high potency statin (Atorvastatin and Rosuvastatin) amongst elderly patient with diabetes.

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Effect of Age and Gender on Pharmacokinetics of Atorvastatin in Humans

Cited by 84 publications

References 11 publications

Interpulse growth hormone secretion in the episodic plasma profile causes the sex reversal of cytochrome P450s in senescent male rats

Interpulse growth hormone secretion in the episodic plasma profile causes the sex reversal of cytochrome P450s in senescent male rats

Efficacy of alternate day dosing of atorvastatin

Sex/Gender -Based Pharmacology and Statin Utilization Amongst Elderly Patients with Diabetes

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