Gender differences in Pharmacokinetics of drugs

Male and female show different pharmacokinetic profile for many drugs. In women,  the pharmacokinetics of drugs may be influenced or altered by menstrual cycles, pregnancy,  lactation,  hormonal therapy,  oral contraceptives. Due to these reasons, FDA requested for the fair share and adequate enrollment of women in clinical trials.

Sex differences in Metabolism: Gender differences have been found out in all stages I.e. absorption, distribution, metabolism, and excretion.

Temporal changes in drug meatabolism during pregnancy: A study was done, its objective was to find out the differences in drug meatabolism during pregnant and non pregnant state.

Study design: Subjects were studied at 14-18 weeks of gestation,  24-28 weeks of gestation and 36-40 weeks of gestation and again 6-8 weeks after delivery. 25 subjects completed all the parts and steps involved in the trial.

Salivary caffeine clearance was used as a measure of CYP1A2 activity.  Dextromethorphan O- & N demethylation was used to assess CYP2D6 & CYP3A4 activity, respectively. 

Results: CYP1A2 was seen to have significantly decreased activity at all periods of the pregnancy.  In contrast, CYP2D6 was seen to have an increased activity at all periods of the pregnancy as compared to the post partum period. CYP3A4 was seen to have consistently, significantly increased activity during all stages of pregnancy.  So, the dosing adjustments of a drug during pregnancy will depend upon the drug and the enzyme involved in the metabolism of that drug.

Sex differences in drug absorption: a well known example is the faster alcohol absorption in women than in men. The gastric mucosal enzyme called alcohol dehydrogenase which is responsible for alcohol oxidation is less active in women as compared to men. 

Since, the GIT motility and intestinal transit is slower in women as compared to men, they may need to wait longer between food consumption and medication, if a drug is to be taken empty stomach. Felodipine, captopril, loratidine, ampicillin, all  are the examples of such drugs.

P- glycoprotein (Pgp) is a membrane ATPase transporter protein, present in intestines, liver and kidney and is responsible for the drug efflux and reduced absorption from the GIT. There is a lower hepatic expression of Pgp in women which leads to the higher plasma concentrations of drugs like digoxin and this may explain why there is high mortality rate from digoxin treatment among women patients with heart failure. Concomitant administration of progesterone in women taking hormonal replacement therapy may be at higher risks as progesterone inhibits Pgp and decreases the excretion of digoxin. 

Differences in drug distribution: volume of distribution of certain drugs is different in women as compared to men because women have lower body water content and higher body fat percentage. So, consequently the Vd for lipophilic drugs is usually higher in women.  And Vd for hydrophilic drugs is lower in women.

Differences in drug excretion: Renal blood flow and glomerular filtration rate are higher in men than in women.

CYP450 enzymes & their sex dependant activity: 

1. CYP1A2: enzyme activity… M> W

                       ExampleOlanzapine.

2. 2A6: enzyme activity… W> M

               Example… Nicotine.

3. 2B6: enzyme activity… W> M

               Example… Tamoxifen, Bupropion

4. 2C9: enzyme activity… M=W

               Example… Phenytoin.

5. 2C19: enzyme activity… M=W

                    Example… Imipramine.

6. 2D6: enzyme activity… mostly W> M

               Example… Codeine.

 7. 3A4: enzyme activity… mostly W> M           

             Example… Erythromycin. 

Phase 2 enzymes & their sex dependant activity:

1.UDP- glucuronosyltransferases: enzyme activity… M> W

Example… Oxazepam, acetaminophen. 

2. N- acetyl transferase: enzyme activity…  M <W

Example… Isoniazid.

3. Methyltransferase: enzyme activity… M > W

Example… L dopa, azathioprine.

4. Sulfotransferases: enzyme activity… M > W

Example… acetaminophen.

M= men , W= women.

Despite all these differences, sex related dose recommendations donot exist for many drugs. Pharmacist needs to recognize these aspects and educate the consumers that such differences play significant role in a drug’s behavior in the body. Women might require different dosing regimen as compared to men due to the different pharmacokinetics. 

Reference: 

1.annu Rev Pharmacol Toxicol. 

2.National Institute for child health and Human development network of maternal- fetal Medicine units

3. American Journal of obstetrics and gynecology

4. US Pharmacist

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