\documentclass[11pt,twoside]{article}\makeatletter

\IfFileExists{xcolor.sty}%
  {\RequirePackage{xcolor}}%
  {\RequirePackage{color}}
\usepackage{colortbl}
\usepackage{wrapfig}
\usepackage{ifxetex}
\ifxetex
  \usepackage{fontspec}
  \usepackage{xunicode}
  \catcode`⃥=\active \def⃥{\textbackslash}
  \catcode`❴=\active \def❴{\{}
  \catcode`❵=\active \def❵{\}}
  \def\textJapanese{\fontspec{Noto Sans CJK JP}}
  \def\textChinese{\fontspec{Noto Sans CJK SC}}
  \def\textKorean{\fontspec{Noto Sans CJK KR}}
  \setmonofont{DejaVu Sans Mono}
  
\else
  \IfFileExists{utf8x.def}%
   {\usepackage[utf8x]{inputenc}
      \PrerenderUnicode{–}
    }%
   {\usepackage[utf8]{inputenc}}
  \usepackage[english]{babel}
  \usepackage[T1]{fontenc}
  \usepackage{float}
  \usepackage[]{ucs}
  \uc@dclc{8421}{default}{\textbackslash }
  \uc@dclc{10100}{default}{\{}
  \uc@dclc{10101}{default}{\}}
  \uc@dclc{8491}{default}{\AA{}}
  \uc@dclc{8239}{default}{\,}
  \uc@dclc{20154}{default}{ }
  \uc@dclc{10148}{default}{>}
  \def\textschwa{\rotatebox{-90}{e}}
  \def\textJapanese{}
  \def\textChinese{}
  \IfFileExists{tipa.sty}{\usepackage{tipa}}{}
\fi
\def\exampleFont{\ttfamily\small}
\DeclareTextSymbol{\textpi}{OML}{25}
\usepackage{relsize}
\RequirePackage{array}
\def\@testpach{\@chclass
 \ifnum \@lastchclass=6 \@ne \@chnum \@ne \else
  \ifnum \@lastchclass=7 5 \else
   \ifnum \@lastchclass=8 \tw@ \else
    \ifnum \@lastchclass=9 \thr@@
   \else \z@
   \ifnum \@lastchclass = 10 \else
   \edef\@nextchar{\expandafter\string\@nextchar}%
   \@chnum
   \if \@nextchar c\z@ \else
    \if \@nextchar l\@ne \else
     \if \@nextchar r\tw@ \else
   \z@ \@chclass
   \if\@nextchar |\@ne \else
    \if \@nextchar !6 \else
     \if \@nextchar @7 \else
      \if \@nextchar (8 \else
       \if \@nextchar )9 \else
  10
  \@chnum
  \if \@nextchar m\thr@@\else
   \if \@nextchar p4 \else
    \if \@nextchar b5 \else
   \z@ \@chclass \z@ \@preamerr \z@ \fi \fi \fi \fi
   \fi \fi  \fi  \fi  \fi  \fi  \fi \fi \fi \fi \fi \fi}
\gdef\arraybackslash{\let\\=\@arraycr}
\def\@textsubscript#1{{\m@th\ensuremath{_{\mbox{\fontsize\sf@size\z@#1}}}}}
\def\Panel#1#2#3#4{\multicolumn{#3}{){\columncolor{#2}}#4}{#1}}
\def\abbr{}
\def\corr{}
\def\expan{}
\def\gap{}
\def\orig{}
\def\reg{}
\def\ref{}
\def\sic{}
\def\persName{}\def\name{}
\def\placeName{}
\def\orgName{}
\def\textcal#1{{\fontspec{Lucida Calligraphy}#1}}
\def\textgothic#1{{\fontspec{Lucida Blackletter}#1}}
\def\textlarge#1{{\large #1}}
\def\textoverbar#1{\ensuremath{\overline{#1}}}
\def\textquoted#1{‘#1’}
\def\textsmall#1{{\small #1}}
\def\textsubscript#1{\@textsubscript{\selectfont#1}}
\def\textxi{\ensuremath{\xi}}
\def\titlem{\itshape}
\newenvironment{biblfree}{}{\ifvmode\par\fi }
\newenvironment{bibl}{}{}
\newenvironment{byline}{\vskip6pt\itshape\fontsize{16pt}{18pt}\selectfont}{\par }
\newenvironment{citbibl}{}{\ifvmode\par\fi }
\newenvironment{docAuthor}{\ifvmode\vskip4pt\fontsize{16pt}{18pt}\selectfont\fi\itshape}{\ifvmode\par\fi }
\newenvironment{docDate}{}{\ifvmode\par\fi }
\newenvironment{docImprint}{\vskip 6pt}{\ifvmode\par\fi }
\newenvironment{docTitle}{\vskip6pt\bfseries\fontsize{22pt}{25pt}\selectfont}{\par }
\newenvironment{msHead}{\vskip 6pt}{\par}
\newenvironment{msItem}{\vskip 6pt}{\par}
\newenvironment{rubric}{}{}
\newenvironment{titlePart}{}{\par }

\newcolumntype{L}[1]{){\raggedright\arraybackslash}p{#1}}
\newcolumntype{C}[1]{){\centering\arraybackslash}p{#1}}
\newcolumntype{R}[1]{){\raggedleft\arraybackslash}p{#1}}
\newcolumntype{P}[1]{){\arraybackslash}p{#1}}
\newcolumntype{B}[1]{){\arraybackslash}b{#1}}
\newcolumntype{M}[1]{){\arraybackslash}m{#1}}
\definecolor{label}{gray}{0.75}
\def\unusedattribute#1{\sout{\textcolor{label}{#1}}}
\DeclareRobustCommand*{\xref}{\hyper@normalise\xref@}
\def\xref@#1#2{\hyper@linkurl{#2}{#1}}
\begingroup
\catcode`\_=\active
\gdef_#1{\ensuremath{\sb{\mathrm{#1}}}}
\endgroup
\mathcode`\_=\string"8000
\catcode`\_=12\relax

\usepackage[a4paper,twoside,lmargin=1in,rmargin=1in,tmargin=1in,bmargin=1in,marginparwidth=0.75in]{geometry}
\usepackage{framed}

\definecolor{shadecolor}{gray}{0.95}
\usepackage{longtable}
\usepackage[normalem]{ulem}
\usepackage{fancyvrb}
\usepackage{fancyhdr}
\usepackage{graphicx}
\usepackage{marginnote}

\renewcommand{\@cite}[1]{#1}


\renewcommand*{\marginfont}{\itshape\footnotesize}

\def\Gin@extensions{.pdf,.png,.jpg,.mps,.tif}

  \pagestyle{fancy}

\usepackage[pdftitle={Bioequivalence of of Two Oral Contraceptive Drugs Containing Ethinylestradiol and Drospirenone in Healthy Female Volunteers},
 pdfauthor={}]{hyperref}
\hyperbaseurl{}

	 \paperwidth210mm
	 \paperheight297mm
              
\def\@pnumwidth{1.55em}
\def\@tocrmarg {2.55em}
\def\@dotsep{4.5}
\setcounter{tocdepth}{3}
\clubpenalty=8000
\emergencystretch 3em
\hbadness=4000
\hyphenpenalty=400
\pretolerance=750
\tolerance=2000
\vbadness=4000
\widowpenalty=10000

\renewcommand\section{\@startsection {section}{1}{\z@}%
     {-1.75ex \@plus -0.5ex \@minus -.2ex}%
     {0.5ex \@plus .2ex}%
     {\reset@font\Large\bfseries}}
\renewcommand\subsection{\@startsection{subsection}{2}{\z@}%
     {-1.75ex\@plus -0.5ex \@minus- .2ex}%
     {0.5ex \@plus .2ex}%
     {\reset@font\Large}}
\renewcommand\subsubsection{\@startsection{subsubsection}{3}{\z@}%
     {-1.5ex\@plus -0.35ex \@minus -.2ex}%
     {0.5ex \@plus .2ex}%
     {\reset@font\large}}
\renewcommand\paragraph{\@startsection{paragraph}{4}{\z@}%
     {-1ex \@plus-0.35ex \@minus -0.2ex}%
     {0.5ex \@plus .2ex}%
     {\reset@font\normalsize}}
\renewcommand\subparagraph{\@startsection{subparagraph}{5}{\parindent}%
     {1.5ex \@plus1ex \@minus .2ex}%
     {-1em}%
     {\reset@font\normalsize\bfseries}}


\def\l@section#1#2{\addpenalty{\@secpenalty} \addvspace{1.0em plus 1pt}
 \@tempdima 1.5em \begingroup
 \parindent \z@ \rightskip \@pnumwidth 
 \parfillskip -\@pnumwidth 
 \bfseries \leavevmode #1\hfil \hbox to\@pnumwidth{\hss #2}\par
 \endgroup}
\def\l@subsection{\@dottedtocline{2}{1.5em}{2.3em}}
\def\l@subsubsection{\@dottedtocline{3}{3.8em}{3.2em}}
\def\l@paragraph{\@dottedtocline{4}{7.0em}{4.1em}}
\def\l@subparagraph{\@dottedtocline{5}{10em}{5em}}
\@ifundefined{c@section}{\newcounter{section}}{}
\@ifundefined{c@chapter}{\newcounter{chapter}}{}
\newif\if@mainmatter 
\@mainmattertrue
\def\chaptername{Chapter}
\def\frontmatter{%
  \pagenumbering{roman}
  \def\thechapter{\@roman\c@chapter}
  \def\theHchapter{\roman{chapter}}
  \def\thesection{\@roman\c@section}
  \def\theHsection{\roman{section}}
  \def\@chapapp{}%
}
\def\mainmatter{%
  \cleardoublepage
  \def\thechapter{\@arabic\c@chapter}
  \setcounter{chapter}{0}
  \setcounter{section}{0}
  \pagenumbering{arabic}
  \setcounter{secnumdepth}{6}
  \def\@chapapp{\chaptername}%
  \def\theHchapter{\arabic{chapter}}
  \def\thesection{\@arabic\c@section}
  \def\theHsection{\arabic{section}}
}
\def\backmatter{%
  \cleardoublepage
  \setcounter{chapter}{0}
  \setcounter{section}{0}
  \setcounter{secnumdepth}{2}
  \def\@chapapp{\appendixname}%
  \def\thechapter{\@Alph\c@chapter}
  \def\theHchapter{\Alph{chapter}}
  \appendix
}
\newenvironment{bibitemlist}[1]{%
   \list{\@biblabel{\@arabic\c@enumiv}}%
       {\settowidth\labelwidth{\@biblabel{#1}}%
        \leftmargin\labelwidth
        \advance\leftmargin\labelsep
        \@openbib@code
        \usecounter{enumiv}%
        \let\p@enumiv\@empty
        \renewcommand\theenumiv{\@arabic\c@enumiv}%
	}%
  \sloppy
  \clubpenalty4000
  \@clubpenalty \clubpenalty
  \widowpenalty4000%
  \sfcode`\.\@m}%
  {\def\@noitemerr
    {\@latex@warning{Empty `bibitemlist' environment}}%
    \endlist}

\def\tableofcontents{\section*{\contentsname}\@starttoc{toc}}
\parskip0pt
\parindent1em
\def\Panel#1#2#3#4{\multicolumn{#3}{){\columncolor{#2}}#4}{#1}}
\newenvironment{reflist}{%
  \begin{raggedright}\begin{list}{}
  {%
   \setlength{\topsep}{0pt}%
   \setlength{\rightmargin}{0.25in}%
   \setlength{\itemsep}{0pt}%
   \setlength{\itemindent}{0pt}%
   \setlength{\parskip}{0pt}%
   \setlength{\parsep}{2pt}%
   \def\makelabel##1{\itshape ##1}}%
  }
  {\end{list}\end{raggedright}}
\newenvironment{sansreflist}{%
  \begin{raggedright}\begin{list}{}
  {%
   \setlength{\topsep}{0pt}%
   \setlength{\rightmargin}{0.25in}%
   \setlength{\itemindent}{0pt}%
   \setlength{\parskip}{0pt}%
   \setlength{\itemsep}{0pt}%
   \setlength{\parsep}{2pt}%
   \def\makelabel##1{\upshape ##1}}%
  }
  {\end{list}\end{raggedright}}
\newenvironment{specHead}[2]%
 {\vspace{20pt}\hrule\vspace{10pt}%
  \phantomsection\label{#1}\markright{#2}%

  \pdfbookmark[2]{#2}{#1}%
  \hspace{-0.75in}{\bfseries\fontsize{16pt}{18pt}\selectfont#2}%
  }{}
      \def\TheFullDate{2011-08-02 (revised: 02 August 2011)}
\def\TheID{\makeatother }
\def\TheDate{2011-08-02}
\title{Bioequivalence of of Two Oral Contraceptive Drugs Containing Ethinylestradiol and Drospirenone in Healthy Female Volunteers}
\author{}\makeatletter 
\makeatletter
\newcommand*{\cleartoleftpage}{%
  \clearpage
    \if@twoside
    \ifodd\c@page
      \hbox{}\newpage
      \if@twocolumn
        \hbox{}\newpage
      \fi
    \fi
  \fi
}
\makeatother
\makeatletter
\thispagestyle{empty}
\markright{\@title}\markboth{\@title}{\@author}
\renewcommand\small{\@setfontsize\small{9pt}{11pt}\abovedisplayskip 8.5\p@ plus3\p@ minus4\p@
\belowdisplayskip \abovedisplayskip
\abovedisplayshortskip \z@ plus2\p@
\belowdisplayshortskip 4\p@ plus2\p@ minus2\p@
\def\@listi{\leftmargin\leftmargini
               \topsep 2\p@ plus1\p@ minus1\p@
               \parsep 2\p@ plus\p@ minus\p@
               \itemsep 1pt}
}
\makeatother
\fvset{frame=single,numberblanklines=false,xleftmargin=5mm,xrightmargin=5mm}
\fancyhf{} 
\setlength{\headheight}{14pt}
\fancyhead[LE]{\bfseries\leftmark} 
\fancyhead[RO]{\bfseries\rightmark} 
\fancyfoot[RO]{}
\fancyfoot[CO]{\thepage}
\fancyfoot[LO]{\TheID}
\fancyfoot[LE]{}
\fancyfoot[CE]{\thepage}
\fancyfoot[RE]{\TheID}
\hypersetup{citebordercolor=0.75 0.75 0.75,linkbordercolor=0.75 0.75 0.75,urlbordercolor=0.75 0.75 0.75,bookmarksnumbered=true}
\fancypagestyle{plain}{\fancyhead{}\renewcommand{\headrulewidth}{0pt}}

\date{}
\usepackage{authblk}

\providecommand{\keywords}[1]
{
\footnotesize
  \textbf{\textit{Index terms---}} #1
}

\usepackage{graphicx,xcolor}
\definecolor{GJBlue}{HTML}{273B81}
\definecolor{GJLightBlue}{HTML}{0A9DD9}
\definecolor{GJMediumGrey}{HTML}{6D6E70}
\definecolor{GJLightGrey}{HTML}{929497} 

\renewenvironment{abstract}{%
   \setlength{\parindent}{0pt}\raggedright
   \textcolor{GJMediumGrey}{\rule{\textwidth}{2pt}}
   \vskip16pt
   \textcolor{GJBlue}{\large\bfseries\abstractname\space}
}{%   
   \vskip8pt
   \textcolor{GJMediumGrey}{\rule{\textwidth}{2pt}}
   \vskip16pt
}

\usepackage[absolute,overlay]{textpos}

\makeatother 
      \usepackage{lineno}
      \linenumbers
      
\begin{document}

             \author[1]{Dr.Eduardo Abib  Junior}

             \affil[1]{  State University of Campinas}

\renewcommand\Authands{ and }

\date{\small \em Received: 25 June 2011 Accepted: 18 July 2011 Published: 2 August 2011}

\maketitle


\begin{abstract}
        


The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol and drospirenone were investigated in 36 healthy female volunteers after oral single-dose administration. The study was performed according to a single-center, randomized, single-dose, 2-way cross-over design with a wash-out phase of 28 days. Blood samples for pharmacokinetic profiling were taken post-dose up to 72 h (ethinylestradiol) and 144 h (drospirenone). Ethinylestradiol and drospirenone plasma concentrations were determined with a validated LC-MS/MS method. Bioequivalence between the products was determined by calculating 90% confidence intervals (90% I.C) for the ratio of AUC0-t and Cmax values for the test and reference products, using logarithmic transformed data. The 90% confidence intervals of ethinylestradiol were 89.13% â??" 95.32%, and 88.13% â??" 96.38%, respectively. The 90% confidence intervals of drospirenone were 94.50% â??" 102.12%, and 95.11% â??" 111.11%, respectively. Since the 90% confidence intervals for Cmax and AUC0-t were within the 80 â??" 125% interval proposed by Food and Drug Administration, it was concluded that the two ethinylestradiol and drospirenone formulations are bioequivalent in their rate and extent of absorption.

\end{abstract}


\keywords{Bioequivalence, Ethinylestradiol, Drospirenone, Contraceptive drugs.}

\begin{textblock*}{18cm}(1cm,1cm) % {block width} (coords) 
\textcolor{GJBlue}{\LARGE Global Journals \LaTeX\ JournalKaleidoscope\texttrademark}
\end{textblock*}

\begin{textblock*}{18cm}(1.4cm,1.5cm) % {block width} (coords) 
\textcolor{GJBlue}{\footnotesize \\ Artificial Intelligence formulated this projection for compatibility purposes from the original article published at Global Journals. However, this technology is currently in beta. \emph{Therefore, kindly ignore odd layouts, missed formulae, text, tables, or figures.}}
\end{textblock*}


\let\tabcellsep& 	 	 		 
\section[{INTRODUCTION}]{INTRODUCTION}\par
ombination contraceptives are most effective means for contraception excluding sterilization. Contraceptives are hormonal agents; combination oral contraceptives contain both an estrogen (ethinylestradiol or mestranol) and a progestogen (many different progestogens are utilized throughout the world). Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. These will vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), through a negative feedback mechanism. Drospirenone is a synthetic progestin and spironolactone analog with antimineralocorticoid activity. In animals and in vitro, drospirenone has antiandrogenic activity, but no glucocorticoid, antiglucocorticoid, estrogenic, or androgenic activity. Progestins counter estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue. \hyperref[b0]{[1]}\hyperref[b1]{[2]}\hyperref[b2]{[3]}\hyperref[b20]{[4]}\hyperref[b3]{[5]} The primary estrogen used in oral contraceptives is ethinylestradiol. 17-Ethinylestradiol (EE), a synthetic estrogen developed in 1938, is an essential constituent of oral contraceptives, which have been widely prescribed since the 1970s. \hyperref[b4]{6} In general, ethinylestradiol is used in combination to prevent pregnancy in women. \hyperref[b6]{7,}\hyperref[b7]{8} The mean bioavailability of EE is reported to be 45\%. \hyperref[b8]{9,}\hyperref[b9]{10} Its metabolism occurs mainly in the liver and at least 10 metabolites of 17EE have been isolated from human urine, with the 2-hydroxy species being the major metabolites. \hyperref[b10]{11,}\hyperref[b11]{12} Drospirenone is a novel synthetic progestogen with a pharmacological profile similar to that of natural progesterone.\par
An analog of spironolactone, drospirenone has antimineralocorticoid and antiandrogenic activity. \hyperref[b13]{[13]}\hyperref[b14]{[14]}\hyperref[b15]{[15]}\hyperref[b16]{[16]} {\ref [17]} It is almost completely metabolized: less than 1\% of the administered dose is excreted in the urine as unchanged drug. The metabolites of drospirenone undergo both hepatic and renal elimination. Based on receptor-binding studies, the metabolites excreted in urine are devoid of pharmacologic activity. \hyperref[b18]{[18]} {\ref [19]}\hyperref[b21]{[20]} The compound is part of certain birth control formulations. Combined with ethinyl estradiol in oral contraceptive formulations, drospirenone-containing contraceptives have similar efficacy and safety profiles to other low-dose oral contraceptives, but seem to offer improved tolerability with regard to weight gain, mood changes, acne and treatment of a severe form of the premenstrual syndrome called premenstrual dysphoric disorder . \hyperref[b22]{21,}\hyperref[b23]{22} The aim of this study was to compare in healthy volunteers, the pharmacokinetics profiles and evaluate the bioequivalence of one test formulation containing 0.02 mg of ethinylestradiol and 3 mg of drospirenone, (test formulation). The test formulation was compared to one commercial formulation containing 0.02 mg of   
\section[{RESULTS}]{RESULTS} 
\section[{a) Demography and safety}]{a) Demography and safety}\par
Thirty one of the 36 enrolled subjects completed the study. Two subject dropped out after phase two for personal reasons. Three subjects dropped out before confinement for personal reasons and abnormal clinical laboratory investigations. Hence 31 completed cases for both treatments were available for analysis of ethinylestradiol and drospirenone plasma concentrations.The demographic characteristics of the study subjects are presented in Table  {\ref 1}, including age, height, weight and BMI. Ethinylestradiol and drospirenone were well tolerated at the administered dose. No serious adverse events occurred. 
\section[{b) Pharmacokinetic and Statistical Analysis}]{b) Pharmacokinetic and Statistical Analysis}\par
The mean (± SD) plasma concentration-time profiles are presented in Figure  {\ref 01} (ethinylestradiol) and Figure  {\ref 02} (drospirenone) and the pharmacokinetic parameters of both substances are summarized in Table  {\ref 2} and Table  {\ref 3}.\par
The mean of Cmax of ethinylestradiol was 84.31 pg/mL in reference product and 77.76 pg/mL in test product. Both occurred 1.25 h after dose administration. Cmax of drospirenone was on average 56947.08 pg/mL in reference product and 58431.17 pg/mL in test product and occurred 1.25 h after dosing (reference) and 1 h (test). For ethinylestradiol, the geometric means of AUC0-?, a measure of extent of absorption amount, were 854.86 pg.h/mL (reference) and 794.61 pg.h/mL (test). The geometric means of AUC0-? of drospirenone were 906099.00 pg.h/mL (reference) and 889520.52 pg.h/mL (test). The values of AUC0-t for ethinylestradiol were 807.17 pg.h/mL (reference) and 746.06 pg.h/mL (test). In the drospirenone evaluation the amounts of AUC0-t were 851151.59 pg.h/mL (reference) and 835564.88 pg.h/mL (test). No significant differences with respect to drug absorption were found. Elimination halflives and elimination rate constants were well comparable between the different preparations.\par
The resulting 90\% confidence intervals of the parameter ratios for for AUC 0-? , AUC 0-t and C max as well as for differences in t max are summarized in Table  {\ref 4}. 
\section[{III.}]{III.} 
\section[{DISCUSSION}]{DISCUSSION}\par
Preventing unwanted pregnancy has been an important issue for women and their families all over the world for many hundreds of years. With the development of oral hormonal contraceptives, the so-called "Pill", in the early 1960s, women finally had access to a revolutionary method of contraception. \hyperref[b24]{23,}\hyperref[b25]{24} Combined oral contraceptives are effective in normalizing irregular periods, reducing symptoms of premenstrual dysphoric disorder, improving acne, and allowing women to avoid having their period at inconvenient times. \hyperref[b26]{25} Combinations of drospirenone and estradiol, when compared with estradiol alone, were protective against endometrial hyperplasia. This combination was also effective in reducing menopausal symptoms, thereby elucidating improvements in health-related quality of life measures without significant adverse drug events. \hyperref[b27]{26} Ethinylestradiol and drospirenone not only prevents pregnancy but also results in shorter, lighter periods, reduced cramps and a regular menstrual cycle. It also helps with some symptoms of premenstrual dysphoric disorder and helps control mild to moderate acne breakouts. \hyperref[b28]{27,}\hyperref[b29]{28} When a new oral contraceptive formulation is developed, it is crucial to ensure optimum hormone exposure during concomitant therapy with other substances, while also guaranteeing the lowest dose to prevent pregnancy and avoid side effects. To enable testing that can deal with these concerns a highly sensitive analytical method with a low limit of quantification (LLOQ) is required to accurately measure oral contraceptives concentrations in human plasma samples.\par
Immunoassay methods have been the most sensitive analytical procedures available for the determination of estrogens in biological samples for many years. \hyperref[b30]{29,}\hyperref[b31]{30} These methods are sensitive, but are time consuming and prone to cross reactivity by steroids and their metabolites. Gas chromatographic coupled to mass spectrometric (GC-MS) methods typically employ some type of extraction, and one or multiple steps of derivatization. \hyperref[b32]{[31]}\hyperref[b33]{[32]}\hyperref[b43]{[33]}\hyperref[b44]{[34]} Recently, liquid chromatography with tandem mass spectrometric (LC-MS/MS ) detection has been applied for the quantitative analysis of estrogens in environmental and biological samples. \hyperref[b34]{[35]}\hyperref[b35]{[36]}\hyperref[b36]{[37]}\hyperref[b37]{[38]}\hyperref[b38]{[39]}\hyperref[b39]{[40]}\hyperref[b40]{[41]} LC-MS/MS is superior to immunoassay methods or GC/MS in terms of simplicity, sensitivity, selectivity and analytical throughput.\par
The LC-MS/MS method described here is specific due to the inherent selectivity of tandem mass spectrometry is in accordance with both Food and Drug Administration (FDA) and the National Sanitary Surveillance Agency (ANVISA) requirements for pharmacokinetic studies. This method offers the advantage over those previously reported using LC-MS/MS \hyperref[b34]{35,}\hyperref[b37]{38,}\hyperref[b39]{40,}\hyperref[b41]{42,} {\ref 43} , showing a low validated LOQ 1 pg mL ?1 (ethinylestradiol) and LOQ 250 pg mL ?1 (drospirenone).\par
The mean ratio of parameters C max and AUC 0-t and 90\% confidence intervals of correspondents were calculated to determine the bioequivalence. The point estimator and the 90\% confidence intervals for the AUC 0t ratio (test/reference: 92.17\% [89.13\% -95.32\%]) indicate high similarity of both formulations with respect to the extent of ethinylestradiol exposure. A high degree of similarity was also observed for C max of ethinylestradiol, as the point estimator and the 90\% confidence interval for the C max ratio are 92.16\% (88.13\% -96.38\%). Regarding the AUC 0-t ratio of drospirenone, the point estimator is 98.24\% and the 90\% confidence interval 94.50\% -102.12\%. Furthermore, exchangeability of both formulations is also suggested by the point estimator and 90\% confidence of C max of this active agent (102.80\% [95.11\% -111.11\%]).\par
The AUC 0-t and AUC 0-inf are both recognized as an uncontaminated measurement of the extent of absorption. The present study showed that 90\% CI of mean AUC 0-t and AUC 0-inf (after log-transformation of individual ratios) were included into the bioequivalence range (80-125\%), consequently, the two formulations of ethinylestradiol and drospirenone are equivalent for the extend of absorption.\par
The statistical comparison of Cmax, AUC0-t and AUC0-inf clearly indicated no significant difference in the two formulations of ethinylestradiol and drospirenone. 90\% confidence intervals for the mean ratio (T/R) of Cmax, AUC0-t and AUC0-inf were entirely is in accordance with both acceptance range the Food and Drug Administration (FDA) and the National Sanitary Surveillance Agency (ANVISA). Based on the pharmacokinetic and statistical results of this study, we can conclude that ethinylestradiol and drospirenone (Test Formulation) is bioequivalent a formulation reference, and that then the test product can be considered interchangeable in medical practice.\par
IV. 
\section[{METHODS a) Study subjects}]{METHODS a) Study subjects}\par
Thirty six healthy female volunteers were selected for the study. All volunteers were healthy as assessed by physical examination, gynecological examination, electrocardiogram (ECG), oncotic cytology (Papanicolaou) and the following laboratory tests: blood glucose, urea, creatinine, uric acid, alanine and aspartate aminotransferases (ALT and AST), gamma-gluthamil transferase (?-GT), alkaline phosphatase, total billirubin, albumin and total protein, trygliceride, total cholesterol, hemoglobin, hematocrit, total and differential white cell counts, red blood cell counts, platelet counts and routine urinalysis. All subjects were negative for human immunodeficiency virus, and B (except for serological scar) and C hepatitis virus. 
\section[{b) Study procedures}]{b) Study procedures}\par
All subjects gave written informed consent and the study was conducted in accordance with the revised Declaration of Helsinki, the rules of Good Clinical Practice (ICH-GCP) and the Resolutions No. 196/96 and 251/97 of National Health Council -Health Ministry, Brazil. The clinical protocol was approved by the Research Ethics Committee of University of Campinas/Unicamp (São Paulo, Brazil) and the National Sanitary Surveillance Agency (ANVISA).\par
The study was a single dose, two -way randomized crossover design with a 28 days washout period between the doses. During each period, the volunteers were hospitalized at 7:00 p.m. They had the usual evening meal until 9:00 p.m., and an overnight fast (minimum of 10 hours).\par
The subjects were randomly assigned to one of the two treatment sequences. Each treatment consisted of a single dose of two tablets, corresponding to a dose of 0.04 mg ethinylestradiol and 6 mg drospirenone. The double of the daily dose was used, since administration of only 0.02 mg ethinylestradiol and 3 mg drospirenone tends to result in plasma concentrations that are too low for a rating of ethinylestradiol 72 h and of drospirenone 144 h after drug intake.\par
Both treatments were administered orally. Subjects have received 200 mL of water at room temperature with each administration. All volunteers were then fasted for 4 h following drug administration; afterwards a standard lunch was consumed. Standard snack and evening meal were provided 7-8 and 10-12 h after dosing, respectively. No other food was permitted during the confinement period. Liquid consumption was allowed ad libitum 2 h after drug administration.\par
However, xanthine-containing drinks including tea, coffee, and cola were avoided.\par
Blood samples (06 mL) were collected by indwelling catheter into EDTA containing tubes before dosing and 15, 30, 45 min and also 1, 1.25, 1.5, 1.75, 2, 2.50, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144 h post-dosing for ethinylestradiol and drospirenone. The blood samples were centrifuged at 3.000 rpm for 10 min. at 4°C and the plasma decanted and storage at -20°C until assay for their ethinylestradiol and drospirenone content. All samples from a single volunteer were analyzed on the same day in order to avoid interassay variation. Arterial pressure (measured non-invasively with a sphygmomanometer), heart rate and temperature were recorded just before and after drug administration at each full-hour sample collection. 
\section[{c) Chemicals and reagents}]{c) Chemicals and reagents}\par
Ethinylestradiol was purchased from United States Pharmacopea (lot number QOC162, Rockville, Maryland, USA). 17?-Ethinylestradiol-d4 was obtained from CDN Isotopes (lot number H352P54, Pointe-Claire, Quebec, Canada). Drospirenone was purchased from United States Pharmacopea (lot number F0G064, Rockville, Maryland, USA). Drospirenone-d4 was obtained from SynFine Research (lot number S-1211-081A4, Richmond Hill, Ontario, Canada). Acetonitrile, methanol, chlorobutane and hexane (HPLC grade). Ultrapure water was obtained from aMilli-Q system. Blank human blood was collected from healthy, drugfree volunteers. Plasma was obtained by centrifugation of blood treated with the anticoagulant EDTA (BD Vacutainer®, BD, Franklin Lakes, NJ, USA). Blank pooled plasma was prepared and stored at ?20 ?C until needed. Ethinylestradiol and Its internal standard 17?ethinylestradiol-d4 were extracted from aliquot of human plasma by liquid-liquid extraction and derivatization. 1 chlorobutane is added to the samples. The organic phase is evaporated to dryness. The buffer solution of the derivatization and derivatization reagent are added to each sample. Samples is added to the hexane and the samples are centrifuged and vortexed adequately. The organic phase is evaporated to dryness. Samples reconstituted with reconstitution solution prepared with methanol and water type Milli-Q. 
\section[{Global Journal of}]{Global Journal of}
\begin{quote}
Medical Research\end{quote}
\par
Drospirenone is extracted from aliquot of human plasma by solid phase extraction and derivatization procedure. To the plasma samples is added the internal standard working solution prepared in buffer solution. The samples are loaded on the top of activated cartridges and passed through the cartridges by gravity. The compound is eluted from the cartridge using methanol and evaporated to dryness. The methanol, catalyzing solution and the derivatization solution are added to each sample. The samples are mixed adequately and incubated for the derivatization step. The samples are evaporated to dryness and reconstituted with the reconstitution solution prepared with Milli-Q type water and acetonitrile. 
\section[{e) Apparatus}]{e) Apparatus}\par
The ethinylestradiol samples were injected into a Zorbax SB-C18, 4.6 x 50 mm, 3.5 ?m column and a Applied Biosystems Sciex API 5000 tandem mass spectrometer. The mobile A phase was methanol-water (78:22, v/v), acetic acid glacial 0.2\% (v/v), and the mobile phase B was a mixture of acetonitrile 100\% and acetic acid glacial 0.2\% (v/v) The chromatographic condition was a gradient mode performed at 35ºC and at a flow rate of 1 mL/min. for pump n o. 1 and 0.5 mL/min. for pump n o. 2. The mass spectrometer was operated with + ESI and MRM using the optimized transitions 530.3 ? 171.1 for the ethinylestradiol derivate and 534.4 ? 171.1 for the 17?-ethinylestradiol-d4 derivative.\par
The drospirenone samples were injected into a Betasil CN column and a Applied Biosystems Sciex API 5000 tandem mass spectrometer. The chromatographic separation was performed with a gradient, at room temperature and at a flow rate of 1.000 mL/min. The mobile phase A was a mixture of water-acetonitrile (65:35, v/v), formic acid 0.1\% (v/v) and the mobile phase B was a mixture of acetonitrile-water (90:10, v/v), formic acid 0.1\% (v/v). The mass spectrometer was operated with + ESI and MRM using the optimized transitions 500.3 ? 421.2 for the drospirenone derivate and 504.3 ? 425.2 for the drospirenone-d4 derivative. 
\section[{f) Calibration}]{f) Calibration}\par
The calibration range of ethinylestradiol was 1.00-200.00 pg/mL. Calibration standards with 8 concentrations (1.00, 2.00, 4.00, 20.00, 40.00, 80.00, 160.00, 200.00 pg/mL) and quality control standards with 3 concentrations (3.02, 70.42, 150.90 pg/mL) were prepared in human EDTA plasma. The calibration range of drospirenone was 250.00-100000.00 pg/mL. Calibration standards with 8 concentrations (250.00, 500.00, 2500.00, 20000.00, 40000.00, 60000.00, 80000.00, 100000.00 pg/mL) and quality control standards with 3 concentrations (751.50, 30060.00, 70140.00 pg/mL) were prepared in human EDTA plasma. 
\section[{g) Method validation}]{g) Method validation}\par
Quantitation was based on determination of relationship between ethinylestradiol and drospirenone peaks areas and I.S. peaks areas. Selectivity was evaluated by extracting plasma samples of plasma from different volunteers, including a lipemic and hemolysed plasma. Recoveries of ethinylestradiol and drospirenone at the three QC concentrations and I.S. were determined by comparing peak areas of spiked plasma samples with the peak area in solutions prepared with the same nominal concentration. For precision (as relative standard deviation, R.S.D.) and accuracy (as relative error,R.E.) studies, samples were prepared at three QC and were analysed in the same day (intraday precision and accuracy), and analysed in 3 consecutive days (inter-day precision and accuracy).\par
The calibration curves were processed and the correlation coefficient was equal to or greater than 0.9979 (ethinylestradiol) and 0.9947 (drospirenone). In ethinylestradiol the accuracy and precision of backcalculated calibration standard concentrations ranged from 89.94-99.21\% and 1.35-6.81\%, respectively. In drospirenone the accuracy and precision of backcalculated calibration standard concentrations ranged from 85.27-102.84\% and 0.66-3.58\%, respectively. In ethinylestradiol the intra-day accuracy and precision of the quality control samples ranged from 101.68-103.07\% and 3.84-4.26\%. In drospirenone the intra-day accuracy and precision of the quality control samples ranged from 95.55-99.12\% and 2.20-3.70\%. Similar accuracy and precision values were observed during the study sample analysis .\par
The stability of ethinylestradiol was also evaluated in plasma samples kept at -20 °C for 221 days and after being submitted to 2 freeze-thawing cycles (24 h each cycle). The stability of drospirenone was also evaluated in plasma samples kept at -20 °C for 93 days and after being submitted to 2 freeze-thawing cycles (24 h each cycle). All samples described above were compared to freshly prepared ethinylestradiol and drospirenone samples at the same concentration level. All sample analysis were carried out in a GLP-compliant manner and in accordance with the current Brazilian Regulatory Agency (ANVISA) requirements and the US Food and Drug Administration Bioanalytical method validation guidance. describing the elimination phase on a log-linear plot, using the software SAS® Institute (Version 9.1.3). Elimination half-life (T 1/2 ) was derived from this rate constant (T 1/2 = ln (2)/Ke). The maximum observed plasma concentration (C max ) and the time taken to achieve this concentration (T max ) were obtained directly from the curves. The areas under the ethinylestradiol (AUC 0-72h ) and drospirenone (AUC 0-144h ) plasma concentration versus time curves from were calculated by applying the linear trapezoidal rule. In ethinylestradiol extrapolation of these areas to infinity (AUC 0-inf ) was done by adding the value C72/Ke to the calculated AUC 0-72h (where C72=plasma concentration calculated from the log-linear regression equation obtained for the estimation of Ke 72 hours after dose). In drospirenone extrapolation of these areas to infinity (AUC 0-inf ) was done by adding the value C144/Ke to the calculated AUC 0-144h (where C144=plasma concentration calculated from the log-linear regression equation obtained for the estimation of Ke 144 hours after dose).\par
The bioequivalence between both formulations was assessed by calculating individual C max , AUC 0-t , AUC 0-inf and C max /AUC 0-t ratios (test/reference) together with their mean and 90\% confidence intervals (CI) after log transformation of the data. The inclusion of the 90\% CI for the ratio in the 80\% to 125\% range was analyzed by nonparametric (SAS® Institute Version 9.1.3) and parametric (ANOVA) methods.\par
V. ACKNOWLEDGMENTS\begin{figure}[htbp]
\noindent\textbf{}\includegraphics[]{image-2.png}
\caption{\label{fig_0}}\end{figure}
 \begin{figure}[htbp]
\noindent\textbf{}\includegraphics[]{image-3.png}
\caption{\label{figure3}}\end{figure}
 			\footnote{© 2011 Global Journals Inc. (US)} 			\footnote{Volume XI Issue III Version ISeptember} 			\footnote{Volume XI Issue III Version I September} 			\footnote{Volume XI Issue III Version I September} 			\footnote{© 2011 Global Journals Inc. (US) © 2011 Global Journals Inc. (US)} 		 		\backmatter   			  			  			 
\subsection[{Conflict of interest}]{Conflict of interest}\par
The authors declared no conflict of interest.			 			  				\begin{bibitemlist}{1}
\bibitem[ Naturwissenschaften ()]{b5}\label{b5} 	 		\textit{},  	 	 		\textit{Naturwissenschaften}  		1938. 26 p. .  	 
\bibitem[Blode ()]{b18}\label{b18} 	 		‘A 1-year pharmacokinetic investigation of a novel oral contraceptive containing drospirenone in healthy female volunteers’.  		 			H Blode 		.  	 	 		\textit{Eur. J. Contracept. Reprod. Health Care}  		2000. 5 p. .  	 
\bibitem[Borges ()]{b42}\label{b42} 	 		‘A novel and sensitive method for ethinylestradiol quantification in human plasma by high-performance liquid chromatography coupled to atmospheric pressure photoionization (APPI) tandem mass spectrometry: Application to a comparative pharmacokinetics study’.  		 			N C Borges 		.  	 	 		\textit{Journal of Chromatography B}  		2009. 877 p. .  	 
\bibitem[Hermes ()]{b37}\label{b37} 	 		‘A semi-automated 96-well plate method for the simultaneous determination of oral contraceptives concentrations in human plasma using ultra performance liquid chromatography coupled with tandem mass spectrometry’.  		 			L P Hermes 		.  	 	 		\textit{Journal of chromatography B}  		2007. 852 p. .  	 
\bibitem[Back ()]{b30}\label{b30} 	 		‘An investigation of the pharmacokinetics of ethynylestradiol in women using radioimmunoassay’.  		 			D J Back 		.  	 	 		\textit{Contraception}  		1979. 20 p. .  	 
\bibitem[Parsey ()]{b22}\label{b22} 	 		‘An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen’.  		 			K S Parsey 		.  	 	 		\textit{Contraception}  		2000. 61 p. .  	 
\bibitem[Twaddle ()]{b39}\label{b39} 	 		‘Analysis of steroid estrogen conjugates in municipal waste waters by liquid chromatography-tandem mass spectrometry’.  		 			N C Twaddle 		.  	 	 		\textit{Journal of chromatography B}  		2003. 793 p. .  	 
\bibitem[Reddy ()]{b38}\label{b38} 	 		‘Analysis of steroid estrogen conjugates in municipal waste waters by liquid chromatography-tandem mass spectrometry’.  		 			S Reddy 		.  	 	 		\textit{Anal. Chem}  		2005. 77 p. .  	 
\bibitem[Laurie ()]{b26}\label{b26} 	 		‘Benefits of Hormonal Contraception May Extend Beyond Pregnancy Prevention’.  		 			B Laurie 		.  	 	 		\textit{Obstet. Gynecol}  		2010. 115 p. .  	 
\bibitem[Saperstein ()]{b31}\label{b31} 	 		‘Bioequivalence of two oral contraceptive drugs containing norethindrone and ethinyl estradiol’.  		 			S Saperstein 		.  	 	 		\textit{Contraception}  		1989. 40 p. .  	 
\bibitem[Bonn ()]{b0}\label{b0} 	 		‘Bioequivalence Study of Generic Tablet Formulations Containing Ethinylestradiol and Chlormadinone Acetate in Healthy Female Volunteers’.  		 			M Bonn 		.  	 	 		\textit{Arzneimittelforschung}  		2009. 59 p. .  	 
\bibitem[Chromatographic profiling and identification of ethynyl and non-ethynyl compounds Steroids ()]{b12}\label{b12} 	 		‘Chromatographic profiling and identification of ethynyl and non-ethynyl compounds’.  	 	 		\textit{Steroids}  		1975. 25 p. .  	 
\bibitem[Sartoretto ()]{b7}\label{b7} 	 		‘Clinical studies with a low dose estrogen-progestogen combination’.  		 			J N Sartoretto 		.  	 	 		\textit{Contraception}  		1977. 15 p. .  	 
\bibitem[Bhaumik ()]{b41}\label{b41} 	 		‘Determination of drospirenone in human plasma by LC -Tandem -MS’.  		 			U Bhaumik 		.  	 	 		\textit{Chromatographia}  		2008. 68 p. .  	 
\bibitem[Zuehlke ()]{b40}\label{b40} 	 		‘Determination of estrogenic steroids in surface and wastewater applying liquid chromatography-electrospray tandem mass spectrometry’.  		 			S Zuehlke 		.  	 	 		\textit{Journal of separation science}  		2005. 28 p. .  	 
\bibitem[Díaz-Cruz ()]{b33}\label{b33} 	 		‘Determination of estrogens and progestogens by mass spectrometric techniques (GC/MS, LC/MS and LC/MS/MS)’.  		 			M S Díaz-Cruz 		.  	 	 		\textit{J. Mass. Spectrom}  		2003. 38 p. .  	 
\bibitem[Isobe ()]{b36}\label{b36} 	 		‘Determination of estrogens and their conjugates in water using solid-phase extraction followed by liquid chromatography-tandem mass spectrometry’.  		 			T Isobe 		.  	 	 		\textit{Journal of chromatography A}  		2003. 984 p. .  	 
\bibitem[Oelkers ()]{b13}\label{b13} 	 		‘Dihydrospirorenone, a new progestogen with antimineralocorticoid activity: effects on ovulation, electrolyte excretion, and the renin-aldosterone system in normal women’.  		 			W Oelkers 		.  	 	 		\textit{J Clin Endocrinol Metab}  		1991. 73 p. .  	 
\bibitem[Oelkers ()]{b16}\label{b16} 	 		‘Drospirenone, a progestogen with antimineralocorticoid properties: a short review’.  		 			W Oelkers 		.  	 	 		\textit{Mol. Cell. Endocrinol}  		2004. 217 p. .  	 
\bibitem[Ezell ()]{b20}\label{b20} 	 		‘Drospirenone/Estradiol for the Treatment of Menopausal Symptoms. Drug 19’.  		 			N Ezell 		.  	 	 		\textit{Contraception}  		2000. 62 p. .  	 	 (Drospirenone: pharmacology and pharmacokinetics of a unique progestogen) 
\bibitem[References and Rapkin ()]{b17}\label{b17} 	 		‘Drospirenone: a novel progestin’.  		 			References 		,  		 			A J Rapkin 		.  	 	 		\textit{Expert Opin. Pharmacother}  		2007. 8 p. .  	 
\bibitem[Muhn ()]{b15}\label{b15} 	 		‘Drospirenone: a Novel Progestogen with Antimineralocorticoid and Antiandrogenic Activity’.  		 			P Muhn 		.  	 	 		\textit{Ann. N. Y. Acad. Sci}  		1995. 761 p. .  	 
\bibitem[Muhn ()]{b14}\label{b14} 	 		‘Drospirenone: A novel progestogen with antimineralocorticoid and antiandrogenic activity: Pharmacological characterization in animal models’.  		 			P Muhn 		.  	 	 		\textit{Contraception}  		1995. 51 p. .  	 
\bibitem[Schurmann ()]{b21}\label{b21} 	 		‘Effect of Drospirenone on Serum Potassium and Drospirenone Pharmacokinetics in Women With Normal or Impaired Renal Function’.  		 			R Schurmann 		.  	 	 		\textit{J. Clin. Pharmacol}  		2006. 46 p. .  	 
\bibitem[William ()]{b1}\label{b1} 	 		‘Effects of a New Hormone Therapy, Drospirenone and 17-ß-Estradiol, in Postmenopausal Hypertension’.  		 			B William 		.  	 	 		\textit{Hypertension}  		2006. 48 p. .  	 
\bibitem[Koltun ()]{b29}\label{b29} 	 		‘Efficacy and safety of 3 mg drospirenone/20 acne vulgaris: a randomized, doubleblind, placebo-controlled trial’.  		 			W Koltun 		.  	 	 		\textit{Contraception}  		2008. 77 p. .  	 
\bibitem[Huber ()]{b23}\label{b23} 	 		‘Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone’.  		 			J Huber 		.  	 	 		\textit{Eur. J. Contracept. Reprod. Health Care}  		2000. 5 p. .  	 
\bibitem[Keam ()]{b6}\label{b6} 	 		‘Ethinylestradiol/drospirenone: a review of its use as an oral contraceptive’.  		 			S J Keam 		.  	 	 		\textit{Treat. Endocrinol}  		2003. 2 p. .  	 
\bibitem[Christiaens ()]{b35}\label{b35} 	 		‘Fully automated method for the liquid chromatographic-tandem mass spectrometric determination of cyproterone acetate in human plasma using restricted access material for on-line sample clean-up’.  		 			B Christiaens 		.  	 	 		\textit{Journal of chromatography A}  		2004. 1056 p. .  	 
\bibitem[Matejicek ()]{b34}\label{b34} 	 		‘High performance liquid chromatography/ion-trap mass spectrometry for separation and simultaneous determination of ethynylestradiol, gestodene, levonorgestrel, cyproterone acetate and desogestrel’.  		 			D Matejicek 		.  	 	 		\textit{Anal. Chim. Acta}  		2007. 588 p. .  	 
\bibitem[Archer ()]{b27}\label{b27} 	 		‘Long-term safety of drospirenoneestradiol for hormone therapy: A randomized, double-blind, multicenter trial’.  		 			D Archer 		.  	 	 		\textit{Menopause}  		2005. 12 p. .  	 
\bibitem[Giese ()]{b43}\label{b43} 	 		‘Measurement of endogenous estrogens: analytical challenges and recent advances’.  		 			R W Giese 		.  	 	 		\textit{Journal of chromatography A}  		2003. 1000 p. .  	 
\bibitem[Guengerich ()]{b10}\label{b10} 	 		‘Metabolism of 17 alphaethynylestradiol in humans’.  		 			F P Guengerich 		.  	 	 		\textit{Life Sci}  		1981-1988. 1990. 47.  	 
\bibitem[Zhang ()]{b44}\label{b44} 	 		‘Microwave -accelerated derivatization for the simultaneous gas chromatography -mass spectrometric analysis of natural and synthetic estrogenic steroid hormones’.  		 			K Zhang 		.  	 	 		\textit{Journal of chromatography A}  		2007. 1148 p. .  	 
\bibitem[Innhoffen]{b4}\label{b4} 	 		\textit{Neue per os-wirksame weibliche Keimdrüsenhormon-Derivate: 17-Äthinylöstradiol und Pregnene},  		 			H H Innhoffen 		.  		 on-3-ol-17.  		 	 
\bibitem[Foster ()]{b24}\label{b24} 	 		‘Number of oral contraceptive pill packages dispensed, method continuation, and costs’.  		 			D G Foster 		.  	 	 		\textit{Obstet. Gynecol}  		2006. 108 p. .  	 
\bibitem[Rogers ()]{b9}\label{b9} 	 		‘Paracetamol interaction with oral contraceptive steroids: increased plasma concentrations of ethinyloestradiol’.  		 			S M Rogers 		.  	 	 		\textit{Br J Clin Pharmacol}  		1987. 23 p. .  	 
\bibitem[Karara ()]{b2}\label{b2} 	 		\textit{Pharmacokinetics and Pharmacodynamics of Drospirenone-Estradiol Combination Hormone Therapy Product Forecast},  		 			A H Karara 		.  		2006. 31 p. .  	 
\bibitem[Pharmacokinetics and Statistical analysis The first-order terminal elimination rate constant (Ke) was estimated by linear regression from the points Coadministered With Hydrochlorothiazide in Hypertensive Postmenopausal Women J. Clin. Pharmacol ()]{b19}\label{b19} 	 		‘Pharmacokinetics and Statistical analysis The first-order terminal elimination rate constant (Ke) was estimated by linear regression from the points Coadministered With Hydrochlorothiazide in Hypertensive Postmenopausal Women’.  	 	 		\textit{J. Clin. Pharmacol}  		2007. 47 p. .  	 
\bibitem[Sitruk ()]{b3}\label{b3} 	 		‘Pharmacology of oral contraceptives’.  		 			W R Sitruk 		.  	 	 		\textit{Rev. Prat}  		1995. 45 p. .  	 
\bibitem[Rebecca ()]{b32}\label{b32} 	 		‘The effect of food on the bioavailability of norethindrone and ethinyl estradiol from norethindrone acetate/ethinyl estradiol tablets intended for continuous hormone replacement therapy’.  		 			A B Rebecca 		.  	 	 		\textit{J. Clin. Pharmacol}  		2003. 43 p. .  	 
\bibitem[Back ()]{b8}\label{b8} 	 		‘The gut wall metabolism of ethinyloestradiol and its contribution to the presystemic metabolism of ethinyloestradiol in humans’.  		 			D J Back 		.  	 	 		\textit{Br J Clin Pharmacol}  		1982. 13 p. .  	 
\bibitem[Williams]{b11}\label{b11} 	 		\textit{The urinary metabolites of 17aethynylestradiol-9a,11xi-3H in women},  		 			M C Williams 		.  		 	 
\bibitem[Gregoriou ()]{b28}\label{b28} 	 		‘Treatment of hirsutism with combined pill containing drospirenone’.  		 			O Gregoriou 		.  	 	 		\textit{Gynecol. Endocrinol}  		2008. 24 p. .  	 
\bibitem[Smith ()]{b25}\label{b25} 	 		‘Why do women miss oral contraceptive pills? An analysis of women's selfdescribed reasons for missed pills’.  		 			J D Smith 		.  	 	 		\textit{J. Midwifery Womens Health}  		2005. 50 p. .  	 
\end{bibitemlist}
 			 		 	 
\end{document}
