Gender‐Specific Effects on Verapamil Pharmacokinetics and Pharmacodynamics in Humans

Krecic‐Shepard, Mary Ellen; Barnas, C.; Slimko, Jill; Jones, Michael P.; Schwartz, Janice B.

doi:10.1177/00912700022008883

Cited by 111 publications

(69 citation statements)

References 83 publications

(70 reference statements)

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“…The increased bioavailability and decreased clearance of oral verapamil in women compared to men caused a greater reduction in blood pressure and heart rate in women compared to men [ 44 ]. However, another study that examined sex-based pharmacokinetic differences for oral verapamil showed that the reduction in mean arterial blood pressure owing to the drug was closely correlated with its plasma concentration, although without any interaction by sex [ 28 ].…”

Section: Calcium Antagonistsmentioning

confidence: 99%

Gender medicine: a task for the third millennium

Baggio

Corsini

Floreani

et al. 2013

Clinical Chemistry and Laboratory Medicine (CCLM)

175

127

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Gender-specific medicine is the study of how diseases differ between men and women in terms of prevention, clinical signs, therapeutic approach, prognosis, psychological and social impact. It is a neglected dimension of medicine. In this review we like to point out some major issues in five enormous fields of medicine: cardiovascular diseases (CVDs), pharmacology, oncology, liver diseases and osteoporosis.CVDs have been studied in the last decades mainly in men, but they are the first cause of mortality and disability in women. Risk factors for CVD have different impacts in men and women; clinical manifestations of CVD and the influence of drugs on CVD have lot of gender differences. Sex-related differences in pharmacokinetics and pharmacodynamics are also emerging. These differences have obvious relevance to the efficacy and side effect profiles of various medications in the two sexes. This evidence should be considered for drug development as well as before starting any therapy. Gender disparity in cancer incidence, aggressiveness and prognosis has been observed for a variety of cancers and, even if partially known, is underestimated in clinical practice for the treatment of the major types of cancer. It is necessary to systematize and encode all the known data for each type of tumor on gender differences, to identify where this variable has to be considered for the purposes of the prognosis, the choice of treatment and possible toxicity. Clinical data suggest that men and women exhibit differences regarding the epidemiology and the progression of certain liver diseases , i.e., autoimmune conditions, genetic hemochromatosis, non-alcoholic steatohepatitis and chronic hepatitis C. Numerous hypotheses have been formulated to justify this sex imbalance including sex hormones, reproductive and genetic factors. Nevertheless, none of these hypothesis has thus far gathered enough convincing evidence and in most cases the evidence is conflicting. Osteoporosis is an important public health problem both in women and men. On the whole, far more epidemiologic, diagnostic and therapeutic studies have been carried out in women than in men. In clinical practice, if this disease remains underestimated in women, patients ' and physicians ' awareness is even lower for male osteoporosis, for which diagnostic and therapeutic strategies are at present less defined.In conclusion this review emphasizes the urgency of basic science and clinical research to increase our understanding of the gender differences of diseases.

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Section: Calcium Antagonistsmentioning

confidence: 99%

Gender medicine: a task for the third millennium

Baggio

Corsini

Floreani

et al. 2013

Clinical Chemistry and Laboratory Medicine (CCLM)

175

127

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“…Sasaki et al [7] did not find any gender related differences in the pharmacokinetics of verapamil following 80 mg oral dosing with the drug. Krecic-Shepard et al reported that verapamil oral clearance was faster in men compared with women when administered as either a sustained release or a regular release formulation [8,9]. Their findings were in contrast to their previous reports of faster clearance of intravenously administered verapamil in women [6].…”

Section: Discussionmentioning

confidence: 88%

The effect of gender on the pharmacokinetics of verapamil and norverapamil in human

Dadashzadeh

Javadian

Sadeghian

2006

Biopharm & Drug Disp

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The effects of gender on the pharmacokinetics of verapamil and its active metabolite, norverapamil, following single oral dose (80 mg, Isoptin) to 12 healthy male (mean age: 25.75+/-2.42 years, mean body weight: 70.59+/-9.94 kg) and 12 healthy female subjects (mean age: 24.08+/-2.84 years, mean body weight: 56.67+/-5.23 kg) were investigated in the present study. Plasma concentrations of verapamil and norverapamil were analysed using a modified high-pressure liquid chromatography method. Pharmacokinetic parameters were calculated by non-compartmental analysis for each subject. For verapamil the half-life (t1/2) and mean residence time (MRT) were significantly shorter in women than men (p<0.01 and p<0.05, respectively). For other pharmacokinetic parameters of verapamil there were no significant differences between males and females. For norverapamil, t1/2, MRT and time to reach to the maximum plasma concentration (Tmax) showed statistically significant differences between the two genders. The AUC(0-24) and AUC(0-infinity) ratios of norverapamil to verapamil were also calculated. The ratios were significantly higher in women compared with men. These observations indicate that the elimination rate of verapamil is faster in women than men which may be attributed to the higher activity of CYP3A4 or lower activity of P-glycoprotein in women compared with men. A contribution of both factors in the appearance of gender differences in verapamil pharmacokinetics is also possible.

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“…[8][9][10][11] Matsuo et al demonstrated that there is a correlation between the CL tot of cyclosporine and the grade severity of liver disease by Child-Pugh classification in patients with hepatitis. 12) However, it is not easy to utilize these approaches to determine the degree of residual hepatic metabolizing ability in patients, as is also the case with creatinine clearance in patients with renal failure.…”

Section: )mentioning

confidence: 99%

mentioning

confidence: 99%

Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

Yokogawa

Ido

Kurihara

et al. 2006

Biological & Pharmaceutical Bulletin

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In treating patients with hepatic failure, it is necessary to set an appropriate drug dosing schedule to take into account of their altered drug disposition kinetics. However, little work has been done to estimate the decrease of total clearance (CL tot ) in relation to the degree of residual hepatic function. Therefore, there is great need for a suitable marker to quantitatively predict the hepatic metabolic capacity in patients with hepatic failure.In humans, there are five predominant families of cytochrome P450 (CYP) species, CYP1A, CYP2C, CYP2D, CYP2E and CYP3A; all of the isoforms differ in their patterns of drug-metabolizing activity, 1) and the amounts of the isoforms in the liver are altered under conditions of hepatic failure.2) The drug-metabolizing activity of the liver may be evaluated on the basis of the correlation between the clearance and the ratio of the metabolite(s) to unchanged drug after the administration of specific inhibitors of various CYP isoforms.Recently, there have been many reports on the expression levels of CYP isoform mRNAs in human liver collected by hepatobiopsy, but no clear correlation has been found between expression levels and the degree of hepatic failure. 3,4) Finnstrom et al. reported that the expression of CYP mRNA in liver is different from that in blood; therefore, blood cannot serve as a surrogate organ for assessment of the expression of the CYP genes in liver.5) Panduro et al. 6) reported that liver regeneration and fibrosis are related to g-carboxylase activity, which is associated with a prolongation of prothrombin time in plasma in rats treated with CCl 4 . Clinically, indocyanine green is commonly used to assess hepatic function. 7)However, none of these procedures appears to be suitable for predicting the decrease in hepatic metabolic activity in patients with hepatic failure.It has been proposed that the drug-metabolizing activity of the liver can be estimated by means of pharmacokinetic analysis after the administration of various probe drugs for CYP isoforms. [8][9][10][11] Matsuo et al. demonstrated that there is a correlation between the CL tot of cyclosporine and the grade severity of liver disease by Child-Pugh classification in patients with hepatitis. 12) However, it is not easy to utilize these approaches to determine the degree of residual hepatic metabolizing ability in patients, as is also the case with creatinine clearance in patients with renal failure.We previously reported that there is a good correlation between mRNA expression and enzyme activity of various CYP isoforms in the livers of rats with acute hepatic failure induced by various doses of CCl 4 . 13) In that study, we also found a good negative correlation between serum aminotransferase activity (AST) and the hepatic activity of each CYP isoform, though the degree of decrease of CL tot varied markedly among CYP isoforms.Here, we present a novel procedure to predict the decrease of CL tot , including that for unknown drugs, based on an increase in serum AST activity in rats with ac...

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Gender‐Specific Effects on Verapamil Pharmacokinetics and Pharmacodynamics in Humans

Cited by 111 publications

References 83 publications

Gender medicine: a task for the third millennium

Gender medicine: a task for the third millennium

The effect of gender on the pharmacokinetics of verapamil and norverapamil in human

Serum Aminotransferase Activity as a Predictor for Estimation of Total Clearance of Hepatically Metabolized Drugs in Rats with Acute Hepatic Failure

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