Gender-related differences in pharmacokinetics and their clinical significance

Tanaka, E.

doi:10.1046/j.1365-2710.1999.00246.x

Cited by 281Pharmacogenetics and Drug MetabolismSex and Gender in HealthcareDrug Transport and Resistance Mechanisms

Gender-related differences in pharmacokinetics and their clinical significance

Tanaka, E.·1999·Journal of Clinical Pharmacy and Therapeutics

DOI 10.1046/j.1365-2710.1999.00246.x

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Abstract

In this review I have attempted to summarize gender differences in pharmacokinetics involving the cytochrome P450 (CYP) isozymes of young and mature adults, excluding the effects of the menstrual cycle, use of oral contraceptives and pregnancy. Sex differences in drug metabolism and elimination are mainly related to steroid hormone levels. CYP3A4, responsible for the metabolism of over 50% of therapeutic drugs, exhibits higher activity in women than in men. Nonetheless, the absence of a sex difference has been reported by some workers. The activity of several other CYP (CYP2C19, CYP2D6, CYP2E1) isozymes and the conjugation (glucuronidation) activity involved in drug metabolism may be higher in men than in women. Drug metabolism in women is affected by sex-specific factors (menopause, pregnancy and menstruation) in addition to the cigarette smoking, drug ingestion and alcohol consumption that are more commonly observed factors in men. Furthermore, they are affected by physiological factors such as drug absorption, protein binding and elimination. Thus, careful attention should be paid to the side-effects and toxicity arising from sex differences in drug metabolism in clinical situations. Although there are specific ethical considerations regarding carrying out drug trials in women, the relationship between the side-effects and toxicity that may be influenced by hormones during drug metabolism and drug treatment needs further study.

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There are sex-specific differences in the activity and expression of many CYP isoforms.
“Accumulating evidence has shown sex-specific differences in the activity and expression of many CYP isoforms [15,16,17].”
From Effect of Caffeine Consumption on the Risk for Neurological and Psychiatric Disorders: Sex Differences in Human (2020) · cites this paper as [17]
The activity of CYP2C16, CYP2C19, and CYP2D6 isozymes and glucuronidation activity involved in drug metabolism are higher in men than in women.
“The activity of several other CYP (CYP2C16, CYP2C19, and CYP2D6) isozymes and the conjugation (glucuronidation) activity involved in drug metabolism are higher in men than in women [17].”
From Effect of Caffeine Consumption on the Risk for Neurological and Psychiatric Disorders: Sex Differences in Human (2020) · cites this paper as [17]

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Villanueva, C. M., Cantor, K. P., Cordier, S., Jaakkola, J. J. K., King, W. D., Lynch, C. F., Porru, S., & Kogevinas, M. (2004) · Epidemiology · doi:10.1097/01.ede.0000121380.02594.fc · Cited by 522 · see citing works
Let’s talk about sex: Differences in drug therapy in males and females
Madla, C. M., Gavins, F. K. H., Merchant, H. A., Orlu, M., Murdan, S., & Basit, A. W. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.05.014 · Cited by 167 · see citing works
Sex Differences in the Expression of Drug-Metabolizing and Transporter Genes in Human Liver
Yang, L., & Li, Y. (2012) · Journal of Drug Metabolism & Toxicology · doi:10.4172/2157-7609.1000119 · Cited by 135 · see citing works
Effect of Caffeine Consumption on the Risk for Neurological and Psychiatric Disorders: Sex Differences in Human
Jee, H. J., Lee, S. G., Bormate, K. J., & Jung, Y.-S. (2020) · Nutrients · doi:10.3390/nu12103080 · Cited by 111 · see citing works
“The activity of several other CYP (CYP2C16, CYP2C19, and CYP2D6) isozymes and the conjugation (glucuronidation) activity involved in drug metabolism are higher in men than in women [17].”
Background
Alcohol intoxication induces greater reductions in brain metabolism in male than in female subjects
Wang, G., Volkow, N. D., Fowler, J. S., Franceschi, D., Wong, C. T., Pappas, N. R., Netusil, N., Zhu, W., Felder, C., & Ma, Y. (2003) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2003.tb04415.x · Cited by 64 · see citing works

Towards the implementation ofCYP2D6andCYP2C19genotypes in clinical practice: Update and report from a pharmacogenetic service clinic
Müller, D. J., Kekin, I., Kao, A. C.-C., & Brandl, E. J. (2013) · International Review of Psychiatry · doi:10.3109/09540261.2013.838944 · Cited by 80 · see citing works
Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19
Bertilsson, L., Tybring, G., Widén, J., et al. (1997) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.1997.00630.x · Cited by 63 · see citing works
The Effect of CYP2C19 and CYP2D6 Genotypes on the Metabolism of Clomipramine in Japanese Psychiatric Patients
Yokono, A., Morita, S., Someya, T., et al. (2001) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-200112000-00002 · Cited by 42 · see citing works
Cytochrome P-450 2D6 and 2C19 polymorphisms and length of hospitalization in psychiatry.
Kropp, S., Lichtinghagen, R., Winterstein, K., et al. (2006) · PubMed · Cited by 32 · see citing works
Effect of O-desmethylvenlafaxine on the content of cytomicrosome cytochrome P450 (CYP450) enzyme and activity of CYP2D6 and CYP3A4 in rat liver
Liu, M., Yan, Y., Gao, K., et al. (2007) · Europe PMC (PubMed Central)

Authors: Tanaka, E.
Affiliations: University of Tsukuba (JP)
Corresponding author: Tanaka, E.
Venue: Journal of Clinical Pharmacy and Therapeutics
Publisher: Wiley
Published: 1999-10
Volume: 24
Issue: 5
Pages: 339-346
ISSN: 0269-4727 (ISSN-L)
1365-2710
DOI: 10.1046/j.1365-2710.1999.00246.x
OpenAlex: W2008637373
Cited by: 281
References: 95
Citations by year: 2026: 11 · 2025: 12 · 2024: 10 · 2023: 11 · 2022: 12 · 2021: 10 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 10 · 2016: 4 · 2015: 8 · 2014: 13 · 2013: 12 · 2012: 11
FWCI: 1.01
Type: journal article
Language: en
Open access: closed
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 5814 d)
Locations: Journal of Clinical Pharmacy and Therapeutics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: sex differences in pharmacokinetics, cytochrome P450 isozymes, CYP3A4, CYP2C19, CYP2D6, CYP2E1, glucuronidation, steroid hormones, menopause, pregnancy, menstrual cycle, drug metabolism, drug elimination, protein binding, drug absorption, drug toxicity
MeSH terms: Cytochrome P-450 Enzyme System, Pharmaceutical Preparations, Female, Humans, Isoenzymes, Male, Pharmacokinetics, Pregnancy, Sex Characteristics

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Gender-related differences in pharmacokinetics and their clinical significance

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