Non-steroidal anti-inflammatory drugs: restrictive or non-restrictive hepatic clearance?

Based on their hepatic extraction ratio and unbound fraction in plasma or blood, drugs can be categorized as being restrictively or non-restrictively eliminated. The general perception is that drugs with very small plasma clearances and extensive plasma protein binding, such as warfarin, are eliminated restrictively. However, based on literature data for 18 non-steroidal anti-inflammatory drugs (NSAIDs) with low plasma clearances (< 60 ml/min), we have shown that most of these low-extraction compounds are non-restrictively eliminated, i.e. their hepatic extraction ratio exceeds their unbound fraction in plasma. For 4 NSAIDs considered in this survey, i.e. phenylbutazone and the oxicams piroxicam, isoxicam and tenoxicam, the hepatic extraction ratio is smaller than their unbound fraction in plasma, and their hepatic elimination, therefore, is restrictive. Our conclusion that most low-clearance NSAIDs are non-restrictively extracted is based on a number of realistic assumptions concerning their pharmacokinetic characteristics: 1. their elimination is exclusively hepatic, 2. bioavailability of their oral dosage form is complete, and 3. they do not undergo extensive reversible biotransformation or enterohepatic circulation.