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Introduction: Pregnancy alters the systemic exposure and clearance of many hepatically cleared drugs that are commonly used by obstetric patients. Understanding the molecular mechanisms underlying the changes in factors that affect hepatic drug clearance (blood flow, protein binding, and intrinsic clearance) is essential to more precisely predict systemic drug exposure and dose requirements in obstetric patients., Areas Covered: This review (1) summarizes the anatomic, physiologic, and biochemical changes in maternal hepatic, cardiovascular, endocrine, and renal systems relevant to hepatic drug clearance and (2) reviews the molecular mechanisms underlying the altered hepatic metabolism and intrinsic clearance of drugs during pregnancy via a comprehensive PubMed search. It also identifies knowledge gaps in the molecular mechanisms and factors that modulate hepatic drug clearance during pregnancy., Expert Opinion: Pharmacokinetic studies have shown that pregnancy alters systemic exposure, protein binding, and clearance of many drugs during gestation in part due to pregnancy-associated decreases in plasma albumin, increases in organ blood flow, and changes in the activity of drug-metabolizing enzymes (DMEs) and transporters. The changes in the activity of certain DMEs and transporters during pregnancy are likely driven by hormonal-changes that inhibit their activity or alter the expression of these proteins through activation of transcription factors.

In neurovascular settings, including treatment and prevention of ischemic stroke and prevention of thromboembolic complications after percutaneous neurointerventional procedures, dual antiplatelet therapy with a P2Y12 inhibitor and aspirin is the standard of care. Clopidogrel remains the most commonly prescribed P2Y12 inhibitor for neurovascular indications. However, patients carrying CYP2C19 no-function alleles have diminished capacity for inhibition of platelet reactivity due to reduced formation of clopidogrel's active metabolite. In patients with cardiovascular disease undergoing a percutaneous coronary intervention, CYP2C19 no-function allele carriers treated with clopidogrel experience a higher risk of major adverse cardiovascular outcomes, and multiple large prospective outcomes studies have shown an improvement in clinical outcomes when antiplatelet therapy selection was guided by CYP2C19 genotype. Similarly, accumulating evidence has associated CYP2C19 no-function alleles with poor clinical outcomes in clopidogrel-treated patients in neurovascular settings. However, the utility of implementing a genotype-guided antiplatelet therapy selection strategy in the setting of neurovascular disease and the clinical outcomes evidence in neurointerventional procedures remains unclear. In this review, we will (1) summarize existing evidence and guideline recommendations related to CYP2C19 genotype-guided antiplatelet therapy in the setting of neurovascular disease, (2) evaluate and synthesize the existing evidence on the relationship of clinical outcomes to CYP2C19 genotype and clopidogrel treatment in patients undergoing a percutaneous neurointerventional procedure, and (3) identify knowledge gaps and discuss future research directions., (© 2025 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)