Table 1.

Changes in pharmacokinetics in patients with CKD (15,36,46,47)

Process	Example Drugs	Anatomic Location	Alteration to This Process in CKD	Potential Change in Kinetics with CKD	Potential Implications for Dosing Regimen
Absorption and bioavailability
Passive: concentration-dependent absorption	Multiple	Enterocytes	Decrease or increase	Decreased or increased bioavailability	Increased or decreased dose
Enzymatic metabolism (multiple; in particular, CYP3A4)	See below	Enterocytes	Decreased	Increased bioavailability	Decrease in dose
Active: P-glycoprotein (ABCB1)	Calcineurin inhibitors, digoxin, methotrexate	Enterocytes	Decreased	Increased bioavailability	Decrease in dose
Distribution
Passive: concentration-dependent diffusion	Multiple	Systemic	No change or increased	No change or increased	No change or increase in initial dose
Protein binding	Multiple	Systemic	Decrease in protein concentration or protein binding	Increase in free (unbound) fraction, which can increase clearance and distribution	Potential increase in dose and either increase or decrease in frequency depending on change in Vd relative to CL
Active transporters (P-glycoprotein; ABCB1)	See above	Liver, brain, elsewhere	Unknown	Decreased activity: increased Vd	No change or increase in initial dose
Drug Clearance
Passive: glomerular filtration	Multiple, including methotrexate	Glomerulus	Decreased	Decreased clearance	Decrease maintenance dose or frequency of dosing
Active: organic anion transporting polypeptide	β-Lactam antibiotics, methotrexate, atorvastatin, imatinib, rosuvastatin	Brain, liver, kidneys, intestine	Decreased	Decreased clearance	Decrease maintenance dose or frequency of dosing
Active: organic cation transporter	Metformin	Liver, kidney, brain, lung, etc.	Decreased	Decreased clearance	Decrease maintenance dose or frequency of dosing
Active: P-glycoprotein (ABCB1)	See above	Liver, kidney	Unknown (decreased in rats)	Decreased clearance	Decrease maintenance dose or frequency of dosing
Enzymatic: CYP2C8/9a	S-Warfarin, fluoxetine, tamoxifen, glipizide	Liver	Decreased or no change	Decreased clearance	Decrease maintenance dose or frequency of dosing
Enzymatic: CYP2C19a	Citalopram, cyclophosphamide, warfarin, diazepam	Liver	Decreased or no change	Decreased clearance	Decrease maintenance dose or frequency of dosing
Enzymatic: CYP2D6a	Carvedilol, metoprolol, tramadol, tamoxifen, codeine	Liver	Decreased	Decreased clearance	Decrease maintenance dose or frequency of dosing
Enzymatic: CYP3A4/5a	Atorvastatin, verapamil, tacrolimus, fluconazole, cyclophosphamide, carbamazepine, tolvaptan	Liver, enterocytes, kidneys (CYP3A5)	Decreased or no change	Decreased clearance	Decrease maintenance dose or frequency of dosing
Enzymatic: CYP1Aa	Caffeine, theophylline, warfarin	Liver	Decreased or no change	Decreased clearance	Decrease maintenance dose or frequency of dosing
Enzymatic: CYP2B6a	Cyclophosphamide, bupropion, methadone	Liver, kidney	Increased or decreased	Increased or decreased clearance	Increase or decrease maintenance dose or frequency of dosing

Vd, volume of distribution;

^aThe effect of CKD on the expression and activity of some cytochrome P450 isoenzymes is controversial and may instead reflect changes in transporter function as discussed in the text. Rowland Yeo et al. (45) found a reduction in cytochrome P450 activity across a range of isoenzymes. However, although some studies have identified progressive reductions in clearance by individual isoenzymes (for example, CYP2D6 [46]), others have found no difference in enzyme activity in advanced CKD for CYP3A4/5 (16,46) and CYP2C9 (47–50). Additional studies in human subjects are required to clarify the extent of any effect.