Abstract
There is an increasing awareness that the exclusion of women from clinical trials may lead to inaccurate application of drug therapy in women. Gender and estrus cycle differences in the pharmacokinetics and pharmacodynamics of drugs in animals have been appreciated for over 60 years, but investigation into these differences in humans has only recently occurred.
It is postulated that hormonal fluctuations within the menstrual cycle phase may be a primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs. Existing data suggest that menstrual cycle variations do occur in renal, cardiovascular, haematological and immune systems. These physiological changes could potentially impact on the pharmacokinetics or pharmacodynamics of drugs by altering properties, such as protein binding or the volume of distribution, and thereby causing significant effects at various times during the menstrual cycle. However, systematic investigations of physiological variability throughout the menstrual cycle are limited.
Fluctuations in symptom severity and clinical course coinciding with the menstrual cycle phase have been seen in some diseases. Hormonal fluctuations within the menstrual cycle have been postulated to cause disease exacerbation. They may also worsen disease severity by impacting on the pharmacokinetics or pharmacodynamics of the medication.
Menstrual cycle hormonal changes may influence drug absorption, distribution, metabolism or excretion. In vivo data to demonstrate an effect of endogenous estrogen or progesterone on pharmacokinetics are limited and contradictory.
Systematic investigations of specific pharmacokinetic and pharmacodynamic changes within the menstrual cycle are lacking. Most published studies have been conducted with small numbers of women and a limited numbers of menstrual cycle phases within 1 menstrual cycle. These design problems have resulted in incomplete data for assessing the effects of the menstrual cycle. To date, there are no demonstrated clinically significant changes that occur in the absorption, distribution or elimination of drugs. With respect to drug metabolism, data are exceedingly sparse and have been collected in a suboptimal fashion. Standardisation of study design and analyses in systematic investigations of the influence of the menstrual cycle on drug pharmacokinetics and pharmacodynamics are needed.
Similar content being viewed by others
References
Nicholas GS, Barron DH. The use of sodium amytal in the production of anesthesia in the rat. J Pharmacol Exp Ther. 1932; 46: 125–9.
Brandstetter Y, Kaplanski J, Leibson V, et al. The effects of estrus cycle on drug metabolism in the rat. Eur J Drug Metab Pharmacokinet. 1986; 11(4): 251–4.
Kato R. Sex-related differences in drug metabolism. Drug Metab Rev. 1974; 3: 1–31.
Skett P. Biochemical basis of sex differences in drug metabolism. Pharmacol Ther. 1988; 38: 269–304.
Gleiter CH, Gundert-Remy U. Gender differences in pharmacokinetics. Eur J Drug Metab Pharmacokinet. 1996; 21: 123–8.
Fletcher CV, Acosta EP, Strykowski JM. Gender differences in human pharmacokinetics and pharmacodynamics. J Adolesc Health. 1994; 15: 619–29.
Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs. 1995; 50(2): 222–39.
Giudicelli JF, Tillement JP. Influence of sex on drug kinetics in man. Clin Pharmacokinet. 1977; 2: 157–66.
Bonate PL. Gender-related differences in xenobiotic metabolism. J Clin Pharmacol. 1991; 31: 684–90.
Food and Drug Administration. Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs. Fed Regist. 1993; 58(139): 39406–16.
Merkatz RB, Temple R, Sobel S, et al. Working Group on Women in Clinical Trials (1993). Women in clinical trials of new drugs: a change in Food and Drug Administration policy. N Engl J Med. 1993; 329: 292–6.
Shaw RW. Neuroendocrinology of the menstrual cycle in humans. Clin Endocrinol Metab 1978 Nov; 7(3): 531–59.
Paaby P, Miller-Petersen J, Larsen CE, et al. Endogenous overnight creatinine clearance, serum β2-microglobulin and serum water during the menstrual cycle. Acta Med Scand. 1987; 221: 191–7.
Nafziger AN, Schwartzman MS, Bertino JS. Absence of tobramycin pharmacokinetic and creatinine clearance variation during the menstrual cycle: implied absence of variation in glomerular filtration rate. J Clin Pharmacol. 1989; 29(8): 757–63.
Forsling M, Akerlun DM, Stromberg P. Variations in plasma concentrations of vasopressin during the menstrual cycle. J Endocrinol. 1981; 89: 263–6.
Katz FH, Romf FTP. Plasma aldosterone and renin activity during the menstrual cycle. J Clin Endocrinol Metab. 1972; 34: 819–23.
Olson BR, Forman MR, Lanza E, et al. Relation between sodium balance and menstrual cycle symptoms in normal women. Ann Intern Med. 1996; 125: 564–7.
Parboosingh J, Doig A, Michie EA. Changes in renal water and electrolyte excretion occurring before and after induced ovulation and their relation to total oestrogen and pregnanediol excretion. J Obstet Gynaecol Br Commonw. 1974; 81(6): 417–22.
Yeko TR, Rao PS, Parsons AK, et al. Atrial natriuretic peptide, oestradiol and progesterone in women undergoing spontaneous and gonadotrophin-stimulated ovulatory cycles. Hum Reprod. 1995; 10(11): 2872–4.
Albano JD, Campbell SK, Farrer A, et al. Gender differences in urinary kallikrein excretion in man: variation throughout the menstrual cycle. Clin Sci. 1994; 86(2): 227–31.
Wald A, Van Thiel DH, Hoeschstetter L, et al. Gastrointestinal transit: effect of the menstrual cycle. Gastroenterology. 1981; 80: 1497–500.
Mones J, Carrio I, Calabuig R, et al. Influence of the menstrual cycle and of menopause on the gastric emptying rate of solids in female volunteers. Eur J Nucl Med. 1993; 20: 600–2.
Hsu JJ, Kin CH, O’Connor MK, et al. Effect of menstrual cycle on esophageal emptying of liquid and solid boluses. Mayo Clin Proc. 1993; 68: 753–6.
Miller SB, Sita A. Parental history of hypertension, menstrual cycle phase, and cardiovascular response to stress. Psychosom Med. 1994; 56: 61–9.
Dunne FP, Barry DG, Ferriss JB, et al. Changes in blood pressure during the normal menstrual cycle. Clin Sci. 1991; 81: 515–8.
Durrington PN. Biological variation in serum lipid concentrations. Scand J Clin Lab Invest 1990; 198 Suppl.: 86–91.
Tersman Z, Collins A, Eneroth P. Cardiovascular responses to psychological and physiological Stressors during the menstrual cycle. Psychosom Med. 1991; 53: 185–97.
Jern C, Manhem K, Eriksson E, et al. Hemostatic responses to mental stress during the menstrual cycle. Thromb Haemost. 1991; 66: 614–8.
Basdevant A, De Lignieres B, Bigorie B, et al. Estradiol, progesterone, and plasma lipids during the menstrual cycle. Diabete Metab. 1981; 7: 1–4.
Reed RG, Pearson TA, Stewart PW, et al. Variance in serum lipids and lipoproteins with menstrual cycle in premenopausal women is no greater than variance in postmenopausal women or men. Circulation. 1995; 91: 923.
Heiling VJ, Jensen MD. Free fatty acid metabolism in the follicular and luteal phases of the menstrual cycle. J Clin Endocrinol Metab. 1992; 74: 806–10.
Pansini F, Piccolo R, Bassi P, et al. Basal and forskolin-stimulated cyclic adenosine monophosphate in intact human platelets during the menstrual cycle. Am J Obstet Gynecol. 1986; 154: 679–82.
Cederblad G, Hahn L, Korsan-Bengtsen K, et al. Variations in blood coagulation, fibrinolysis, platelet function, and various plasma proteins during the menstrual cycle. Haemostasis. 1977; 6: 294–302.
Larsen LF, Andersen HR, Hansen AB, et al. Variation in risk indicators of cardiovascular disease during the menstrual cycle: an investigation of within-subject variation in glutathione peroxidase, homeostatic variables, lipids and lipoproteins in healthy young women. Scand J Clin Lab Invest. 1996; 56: 241–9.
Mathur S, Mathur RS, Goust JM, et al. Cyclic variations in white cell subpopulations in the human menstrual cycle: correlations with progesterone and estradiol. Clin Immunol Immunopathol. 1979; 13: 246–53.
Bisdee JT, Garlick PJ, James WPT. Metabolic changes during the menstrual cycle. Br J Nutr. 1989; 61: 641–50.
Christy NP, Shaver JC. Estrogens and the kidney. Kidney Int. 1974; 6: 366–76.
Harvey AM, Malvin RL, Vander AJ. Comparison of creatinine secretion in men and women. Nephron. 1966; 3: 201–5.
Davidson JM, Noble MCB. Serial changes in 24 hour creatinine clearance during normal menstrual cycle and the first trimester of pregnancy. Br J Obstet Gynaecol. 1981; 88: 10–7.
Singer JS, Brandt LJ. Pathophysiology of the gastrointestinal tract during pregnancy. Am J Gastroenterol. 1991; 86: 1695–712.
Hutson WR, Roehrkasse RL, Wald A. Influence of gender and menopause on gastric emptying and motility. Gastroenterology. 1989; 96: 11–7.
Horowitz M, Maddern J, Chatterton E, et al. The normal menstrual cycle has no effect on gastric emptying. Br J Obstet Gynaecol. 1985; 92: 743–6.
Thurnbull GK, Thompson DG, Day S, et al. Relationships between symptoms, menstrual cycle and oro-cecal transit in normal and constipated women. Gut. 1989; 30: 30–4.
Sweeting J. Does the time of the month affect the function of the gut? Gastroenterology. 1992; 102: 1084–5.
Degen LP, Phillips SE. Variability of gastrointestinal transit in healthy women and men. Gut. 1996; 39: 299–305.
Little BC, Zahn TR. Changes in mood and autonomic functioning during the menstrual cycle. Psychophysiology. 1974; 11: 579–90.
Girdler SS, Pedersen CA, Stern RA, et al. The menstrual cycle and premenstrual syndrome: modifiers of cardiovascular reactivity in women. Health Psychol. 1993; 12: 180–92.
Girdler SS, Kight KC. Hemodynamic stress responses in men and women examined as a function of female menstrual cycle phase. Int J Psychophysiol. 1994; 17: 233–48.
Kharitonov SA, Logan-Sinclair RB, Bussett CM, et al. Peak expiratory nitric oxide differences in men and women: relation to the menstrual cycle. Br Heart J. 1994; 72: 243–5.
Kaplan BJ, Whitsett SF, Robinson JW. Menstrual cycle phase is a potential confounder in psychophysiology research. Psychophysiology. 1990; 27: 445–50.
Karpanou EA, Vyssoulis GP, Georgoudi DG, et al. Disparate serum lipid changes between normotensive and hypertensive women during the menstrual cycle. Am J Cardiol. 1992; 70: 111–3.
Schijf CPT, Van der Mooren MJ, Doesburg WH, et al. Difference in serum lipids, lipoprotein, sex hormonc binding globulin and testosterone between the follicular and the luteal phase of the menstrual cycle. Acta Endocrinol. 1993; 129: 130–6.
Lebech AM, Kjaer A, Lebech PE. Metabolic changes during the normal menstrual cycle: a longitudinal study. Am J Obstet Gynecol. 1990; 163: 414–6.
Reed RG, Pearson TA, Stewart PW, et al. Do premenopausal women exhibit significant biologic variability in plasma lipids as a function of menstrual status. Clin Chem 1995; 41; S136.
Clark BA, Elahi D, Epstein FH. The influence of gender, age, and the menstrual cycle on plasma atrial natriuretic peptide. J Clin Endocrinol Metab. 1990; 70: 349–52.
Trigoso WF, Wesly JM, Meranda DL, et al. Vasopressin and atrial natriuretic hormonc response to hypertonic saline during the follicular and luteal phases of the menstrual cycle. Hum Reprod. 1996; 11(11): 2392–5.
Janowsky DS, Berens SC, Davis JM. Correlations between mood, weight, and electrolytes during the menstrual cycle: a renin-angiotensin-aldosterone hypothesis of premenstrual tension. Psychosom Med. 1973; 325: 143–53.
Reeves BD, Garvin JE, McElin TW. Premenstrual tension: symptoms and weight changes related to potassium therapy. Am J Obstet Gynecol. 1971; 109: 1036–41.
Dadlani AG, Chandwani S, Desai CA, et al. Serum electrolytes during various phases of menstrual cycle. Indian J Physiol Pharmacol. 1982; 26: 302–6.
Stephenson LA, Kolka MA, Wilkerson JF. Metabolic and thermoregulatory responses to exercise in menstrual cycles of athletic and non-athletic women. Med Sci Sports Exerc. 1982; 14: 270–5.
Williams CL, Stancel GM. Estrogens and progestins. In: Hardman JG, Limbird LE, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 1411–58.
Gleichauf CN, Roe DA. The menstrual cycle’s effect on the reliability of bioimpedance measurements for assessing body composition. Am J Clin Nutr. 1989; 50: 903–7.
Webb P. 24-hour energy expenditure and the menstrual cycle. Am J Clin Nutr. 1986; 55: 637–40.
Nicklas BJ, Hackney AC, Sharp RL, et al. The menstrual cycle and exercise: performance, muscle glycogen, and substrate responses. Int J Sports Med. 1989; 10: 264–9.
Craft IL, Wise IJ. Changes in amino acid metabolism during the menstrual cycle. J Obstet Gynaecol Br Commonw. 1969; 76: 928–33.
Toth EL, Suthijumroon A, Crockford PM, et al. Insulin action does not change during the menstrual cycle in normal women. J Clin Endocrinol Metab. 1987; 64: 74–80.
Harlow SD, Ephross SA. Epidemiology of menstruation and its relevance to women’s health. Epidemiol Rev. 1995; 17(2): 265–86.
Ansar Ahmed S, Penhale WJ, Talal N. Sex hormones, immune responses, and autoimmune diseases: mechanism of a sex hormonc action. Am J Pathol. 1985; 121: 531–51.
Polan ML, Kuo A, Loukides J, et al. Cultured human luteal peripheral monocytes secrete increased levels of interleukin-1. J Clin Endocrinol Metab. 1990; 70: 480–4.
Leslie CA, Dubey DP. Increased PGE2 from human monocytes isolated in the luteal phase of the menstrual cycle: implications for immunity? Prostaglandins. 1994; 47: 41–54.
Sulke AN, Jones DB, Wood PJ. Variation in natural killer activity in peripheral blood during the menstrual cycle. BMJ (Clin Res Ed). 1985; 290: 884–8.
Moldofsky H, Lue FA, Shahal B, et al. Diurnal sleep/wake-related immune function during the menstrual cycle of healthy young women. J Sleep Res. 1995; 4: 150–9.
Backstrom T, Jorpes P. Serum phenytoin, phenobarbital, carbamazepine, albumin and plasma estradiol progesterone concentrations during the menstrual cycle in women with epilepsy. Acta Neurol Scand. 1979; 58: 63–71.
Boggess KA, Williamson HO, Homm RJ. Influence of the menstrual cycle on systemic diseases. Obstet Gynecol Clin North Am. 1990; 17(2): 321–42.
Serrander AM, Peek KE. Changes in contact lens comfort related to the menstrual cycle and menopause: a review of articles. J Am Optom Assoc. 1993; 64(3): 162–6.
Dalton K. Influence of menstruation on glaucoma. Br J Ophthalmol. 1967; 51(10): 692–5.
Qureshi IA. Intraocular pressure: association with menstrual cycle, pregnancy and menopause in apparently healthy women. Chin J Physiol. 1995; 38(4): 229–34.
Kalogeromitros D, Katsarou A, Armenaka M, et al. Influence of the menstrual cycle on skin-prick test reactions to histamine, morphine and allergen. Clin Exp Allergy. 1995; 25(5): 461–6.
Leibenluft E. Women with bipolar illness: clinical and research issues. Am J Psychiatry. 1996; 153: 163–73.
Smolensky MH, D’Alonzo GE. Medical chronobiology: concepts and applications. Am Rev Respir Dis 1993; 147(6 Pt 2): S2–19.
Gotthardt M, Clark JD, Roy TM. ‘Ovarian asthma’: fact or fancy? J Ky Med Assoc. 1996; 94(3): 105–8.
Eliasson O, Scherzer HH, Jr DeGraff AC. Morbidity in asthma in relation to the menstrual cycle. J Allergy Clin Immunol 1986; 77(1 Pt 1): 87–94.
Gibbs CJ. Coutts II, Lock R, et al. Premenstrual exacerbation of asthma. Thorax. 1984; 39(11): 833–6.
Hanley SP. Asthma variation with menstruation. Br J Dis Chest. 1981; 75(3): 306–8.
Skobeloff EM, Spivey WH, Silverman R, et al. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch Intern Med. 1996; 156(16): 1837–40.
Pauli BD, Reid RL, Munt PW, et al. Influence of the menstrual cycle on airway function in asthmatic and normal subjects. Am Rev Respir Dis. 1989; 140(20): 358–62.
Newnham DM, Wheeldon NM, McFarlane LC, et al. Extrapulmonary β2-responses to intravenous salbutamol during the menstrual cycle. Eur J Clin Pharmacol. 1994; 46: 511–5.
Tan KS, McFarlane LC, Coutie WJ, et al. Effects of exogenous female sex-steroid hormones on lymphocyte beta 2-adrenoceptors in normal females. Br J Clin Pharmacol. 1996; 41(5): 414–6.
Herkes GK, Eadie MJ. Possible roles for frequent salivary antiepileptic drug monitoring in the management of epilepsy. Epilepsy Res. 1990; 6(2): 146–54.
Zimmerman AW. Hormones and epilepsy. Neurol Clin. 1986; 4(4): 853–61.
Rosciszewska D, Buntner B, Guz I, et al. Ovarian hormones, anticonvulsant drugs, and seizures during the menstrual cycle in women with epilepsy. J Neurol Neurosurg Psychiatry. 1986; 49(1): 47–51.
Duncan S, Read CL, Brodie MJ. How common is catamenial epilepsy? Epilepsia. 1993; 34(5): 827–31.
Herkes GK, Eadie MJ, Sharbrough F, et al. Patterns of seizure occurrence in catamenial epilepsy. Epilepsy Res. 1993; 15(1): 47–52.
Morrell MJ. Hormones and epilepsy through the lifetime. Epilepsia. 1992; 22 Suppl. 4: S49–S61.
Herzog AG. Reproductive endocrine considerations and hormonal therapy for women with epilepsy. Epilepsia. 1991; 32 Suppl. 6: S27–S33.
Mattson RH, Cramer JA. Epilepsy, sex hormones, and antiepileptic drugs. Epilapsia. 1985; 26 Suppl. 1: S40–S51.
Backstrom T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand. 1976; 54: 321–47.
Rodriguez Macias KA. Catamenial epilepsy: gynecological and hormonal implications. Five case reports. Gynecol Endocrinol. 1996; 10(2): 139–42.
Jones BM, Jones MK. Alcohol effects in women during the menstrual cycle. Ann NY Acad Sci. 1976; 273: 576–87.
Lammers SMM, Mainzer DEH, Breteler MHM. Do alcohol pharmacokinetics in women vary due to the menstrual cycle? Addiction. 1995; 90(1): 23–30.
Miaskiewicz SL, Shively CA, Vesell ES. Sex differences in absorption kinetics of sodium salicylate. Clin Pharmacol Ther. 1982; 31(1): 30–7.
Jochemsen R, Van der Graaff M, Boeijinga JK, et al. Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam. Br J Clin Pharmacol. 1982; 13(3): 319–24.
Shavit G, Lerman P, Korczyn AD, et al. Phenytoin pharmacokinetics in catamenial epilepsy. Neurology. 1984; 34(7): 959–61.
Daneshmend TK, Jackson L, Roberts CJC. Physiological and pharmacological variability in estimated hepatic blood flow in man. Br J Clin Pharmacol. 1981; 11: 491–6.
Somani SM, Khurana RC. Mechanism of estrogen-imipramine interaction. JAMA. 1973; 223: 560.
Martucci CP, Fishman J. P450 enzymes of estrogen metabolism. Pharmacol Ther. 1993; 57: 237–57.
Waxman DJ. Interactions of hepatic cytochromes P450 with steroid hormones. Biochem Pharmacol. 1988; 37: 71–84.
Walle T, Walle UK, Cowart TD, et al. Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects. Clin Pharmacol Ther. 1989; 46: 257–63.
Miners JO, Atwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clin Pharmacol. 1983; 16: 503–9.
Riester EF, Pantuck EJ, Pantuck CB, et al. Antipyrine metabolism during the menstrual cycle. J Pharmacol Ther. 1980; 28: 384–91.
Kellerman G, Luyten-Kellerman M, Horning MG, et al. Elimination of antipyrine and benzo[a]pyrene metabolism in cultured human lymphocytes. Clin Pharmacol Ther. 1976; 20: 72–80.
Bruguerolle B, Toumi M, Fraj F, et al. Influence of menstrual cycle on theophylline pharmacokinetics in asthmatics. Eur J Clin Pharmacol. 1990; 39(1): 59–61.
Manowitz P, Schull CM. Methaqualone metabolism by rat liver microsomes. Res Commun Chem Pathol Pharmacol. 1976; 13(1): 27–39.
Oram M, Wilson K, Burnett D, et al. Metabolic oxidation of methaqualone in extensive and poor metabolisers of debrisoquine. Eur J Clin Pharmacol. 1982; 23(2): 147–50.
Oram M, Wilson K, Burnett D. The influence of oral contraceptives on the metabolism of methaqualone in man. Br J Clin Pharmacol. 1982; 14(3): 341–5.
Abdu-Aguye I, Dunlop D, Patel P, et al. Propranolol pharmacokinetics during the menstrual cycle. Postgrad Med J. 1986; 62: 1093–5.
Gerdin E, Rane A. N-Demethylation of ethylmorphine in pregnant and non-pregnant women and in men: an evaluation of the effects of sex steroids. Br J Clin Pharmacol. 1992; 34: 250–5.
Zeiner AR, Kegg PS. Menstrual cycle and oral contraceptive effects on alcohol pharmacokinetics in Caucasian females. Curr Alcohol. 1981; 8: 47–56.
Miners JO, Atwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. Br J Clini Pharmacol. 1983; 16: 503–9.
Nayak VK, Kshirsagar NA, Desai KN, et al. Influence of menstrual cycle on antipyrine pharmacokinetics in healthy Indian female volunteers. Br J Clin Pharmacol. 1988; 26(5): 604–6.
Lane JD, Steege JF, Rupp SL, et al. Menstrual cycle effects on caffeine elimination in the human female. Eur J Clin Pharmacol. 1992; 43: 543–6.
Wojcicki J, Gawronska-Szklarz B, Kazimierczyk J, et al. Comparative pharmacokinetics of paracetamol in men and women considering follicular and luteal phases. Arzneimittel Forschung. 1979; 29: 350–2.
Wilson K, Oram M, Horth C, et al. The influence of the menstrual cycle on the metabolism and clearance of methaqualone. Br J Clin Pharmacol. 1982; 14: 333–9.
Brick J, Nathan PE, Westrick E, et al. The effect of menstrual cycle on blood alcohol levels and behavior. J Stud Alcohol. 1986; 47: 472–7.
Kirkwood C, Moore A, Hayes P, et al. Influence of menstrual cycle and gender on alprazolam pharmacokinetics. Clin Pharmacol Ther. 1991; 50(4): 404–9.
Greenblatt DJ, Wright CE. Clinical pharmacokinetics of alprazolam: therapeutic implications. Clin Pharmacokinet. 1993; 24(6): 453–71.
Lew KH, Ludwig EA, Milad MA, et al. Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 1993; 54: 402–14.
Macdonald JL, Herman RJ, Verbeek RK. Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal. Eur J Clin Pharmacol. 1990; 38: 175–9.
Cordaro JA, Morse GD, Bartos L, et al. Zidovudine pharmacokinetics in HIV-positive women during different phases of the menstrual cycle. Pharmacotherapy. 1993; 13(4): 369–77.
Kinney EL, Trautmann J, Gold JA, et al. Underrepresentation of women in new drug trials. Ann Intern Med. 1981; 95: 495–9.
Reinberg A, Smolensky M. Circadian changes of drug disposition in man. Clin Pharmacokinet. 1982; 7: 401–20.
Kawachi I, Colditz GA. Invited commentary: confounding, measurement error, and publication bias in studies of passive smoking. Amer J Epidemiol. 1996; 144(10): 909–15.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kashuba, A.D.M., Nafziger, A.N. Physiological Changes During the Menstrual Cycle and Their Effects on the Pharmacokinetics and Pharmacodynamics of Drugs. Clin Pharmacokinet 34, 203–218 (1998). https://doi.org/10.2165/00003088-199834030-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199834030-00003