Article Text

PDF
Pharmacotherapy: Pharmacokinetics and Pharmacodynamics (including: ADE, TDM, DUE)
Behind CYP450 interaction tables ñ the effect of gender and age on pharmacokinetics
  1. H. Jenzer,
  2. L. Sadeghi,
  3. C. Krause,
  4. F. Pfister,
  5. P. Stute,
  6. Z. Stanga
  1. 1Bern University of Applied Sciences – health division, aR&D Nutrition and Dietetics, Bern, Switzerland 2Bern University Women's Hospital, Department of Gynecologic Endocrinology and Reproductive Medicine, Bern, Switzerland
  2. 3Bern University Hospital, division of Endocrinology Diabetes and Clinical Nutrition and Department of Internal Medicine, Bern, Switzerland

Abstract

Background Interaction tables are restricted to unspecified isoenzymes of the families CYP1, CYP2, and CYP3. Data on gender impact has been required by the FDA only after 1993.

Purpose The aim is to assess the effect of gender and age on pharmacokinetics and to explain inconsistent data reported so far.

Materials and methods A systematic online literature research was performed on the usual platforms. 168 references could be evaluated.

Results Ontogeny, peri- and postnatal phase: CYP450 inducibility begins in the earliest embryonic stage and reaches high rates before birth. Drugs are not distributed freely to all parts of the body in newborns. Childhood: preadolescent fasting boys absorb 35.2%, girls 45% of an oral iron loading dose. This explains the higher prevalence of iron anaemia in boys aged 11-15 (12.1%) compared to equally aged girls (6.1%). Adulthood: mean gastric fasting pH is 2.15 for men and 2.8 for women corresponding to a fivefold H+ activity in men. Women secrete gastrin and bicarbonate at the moment of substrate afflux, men more steadily. Gastric emptying, small intestine motility and colon transit times are downregulated by oestrogen and progesterone. In men, isoenzymes CYP1A2, CYP2C9, CYP2E1 are more active (CYP1A2 up to 40-fold), in women CYP3A4,5,7, CYP2A6, CYP2B6, and CYP2D6 (CYP2D6 only in the fertile phase). CYP3A4,5,7 activity depends on the menstrual cycle and peaks before ovulation and in pregnancy. Hepatic and intestinal P-gp (permeability glycoprotein) is expressed more in men than in women. Confused reports arise if the authors do not account for any mutually opposed effects of P-gp and CYP3A4,5,7. Pharmacokinetics change markedly in pregnancy due to slow motility, haemodynamics, cardiac output, etc. Incomplete protein digestion due to PPI treatment in pregnancy is a documented risk factor for predisposition to immune responses and asthma of the child (5.6% vs 3.7% in the untreated population). Copper absorption is higher in women aged 20-59 (71%) than in men of the same age (64%). This difference between the genders does not exist in the 60-83 age range.

Conclusions Inconsistent data arise from crossed effects of co-localised P-gp and CYP3A4,5,7. Thus, only studies involving drugs that are not transported by P-gp are appropriate in CYP3A4,5,7 studies and vice versa. Interaction tables are limited tools. They do not distinguish between special patient groups or age ranges and thus need improvement.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.